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1. Integrative analysis of multi-omics data reveals importance of collagen and the PI3K AKT signalling pathway in CAKUT

Author

Jumamurat R. Bayjanov, Cenna Doornbos, Ozan Ozisik, Woosub Shin, Núria Queralt-Rosinach, Daphne Wijnbergen, Jean-Sébastien Saulnier-Blache, Joost P. Schanstra, Bénédicte Buffin-Meyer, Julie Klein, José M. Fernández, Rajaram Kaliyaperumal, Anaïs Baudot, Peter A. C. ’t Hoen, and Friederike Ehrhart

Subjects
Medicine, Science
Abstract

Abstract Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) is the leading cause of childhood chronic kidney failure and a significant cause of chronic kidney disease in adults. Genetic and environmental factors are known to influence CAKUT development, but the currently known disease mechanism remains incomplete. Our goal is to identify affected pathways and networks in CAKUT, and thereby aid in getting a better understanding of its pathophysiology. With this goal, the miRNome, peptidome, and proteome of over 30 amniotic fluid samples of patients with non-severe CAKUT was compared to patients with severe CAKUT. These omics data sets were made findable, accessible, interoperable, and reusable (FAIR) to facilitate their integration with external data resources. Furthermore, we analysed and integrated the omics data sets using three different bioinformatics strategies: integrative analysis with mixOmics, joint dimensionality reduction and pathway analysis. The three bioinformatics analyses provided complementary features, but all pointed towards an important role for collagen in CAKUT development and the PI3K-AKT signalling pathway. Additionally, several key genes (CSF1, IGF2, ITGB1, and RAC1) and microRNAs were identified. We published the three analysis strategies as containerized workflows. These workflows can be applied to other FAIR data sets and help gaining knowledge on other rare diseases.

Published
2024
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2. Abcc6 deficiency prevents rhabdomyolysis-induced acute kidney injury

Author

Audrey Casemayou, Julie Belliere, Emmanuel Letavernier, Eloïse Colliou, Hélène El Hachem, Jeremy Zarowski, Dominique Bazin, Clément Kounde, Alexis Piedrafita, Guylène Feuillet, Joost P. Schanstra, and Stanislas Faguer

Subjects
Medicine, Science
Abstract

Abstract Rhabdomyolysis is a risk factor for acute kidney injury, transition towards chronic kidney disease, and death. The role of calcium phosphate deposits in the mechanisms of rhabdomyolysis-induced acute kidney injury (RAKI) is still unclear. Better insight of the role calcium in RAKI could lead to new therapeutic avenues. Here, we show in a mice model of RAKI that calcium phosphate deposits were frequent in the kidney (hydroxyapatite) and partly correlated with the severity of the kidney injury. However, the intensity of deposits was highly heterogeneous between mice. Treatment with sodium chloride, sodium bicarbonate or inorganic pyrophosphate (PPi; an inhibitor of the calcium phosphate crystallization), or combinations thereof, did not improve kidney outcomes and hydroxyapatite deposition during RAKI. Unexpectedly, Abcc6 knockout mice (ko), characterized by PPi deficiency, developed less severe RAKI despite similar rhabdomyolysis severity, and had similar hydroxyapatite deposition suggesting alternative mechanisms. This improved kidney outcome at day 2 translated to a trend in improved glomerular filtration rate at month 2 in Abcc6 -/- mice and to significantly less interstitial fibrosis. In addition, whereas the pattern of infiltrating cells at day 2 was similar between wt and ko mice, kidneys of Abcc6 -/- mice were characterized by more CD19+ B-cells, less CD3+ T-cells and a lower R1/R2 macrophage ratio at month 2. In summary, kidney calcium phosphate deposits are frequent in RAKI but hydration with sodium bicarbonate or sodium chloride does not modify the kidney outcome. Blocking ABCC6 emerges as a new option to prevent RAKI and subsequent transition toward kidney fibrosis.

Published
2023
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3. Urinary peptides provide information about the risk of mortality across a spectrum of diseases and scenarios

Author

Felix Keller, Joachim Beige, Justyna Siwy, Alexandre Mebazaa, Dewei An, Harald Mischak, Joost P. Schanstra, Marika Mokou, Paul Perco, Jan A. Staessen, Antonia Vlahou, and Agnieszka Latosinska

Subjects
Death, Mass spectrometry, Peptidomics, Personalised medicine, Urinary biomarkers, Medicine
Abstract

Abstract Background There is evidence of pre-established vulnerability in individuals that increases the risk of their progression to severe disease or death, although the mechanisms causing this are still not fully understood. Previous research has demonstrated that a urinary peptide classifier (COV50) predicts disease progression and death from SARS-CoV-2 at an early stage, indicating that the outcome prediction may be partly due to vulnerabilities that are already present. The aim of this study is to examine the ability of COV50 to predict future non-COVID-19-related mortality, and evaluate whether the pre-established vulnerability can be generic and explained on a molecular level by urinary peptides. Methods Urinary proteomic data from 9193 patients (1719 patients sampled at intensive care unit (ICU) admission and 7474 patients with other diseases (non-ICU)) were extracted from the Human Urinary Proteome Database. The previously developed COV50 classifier, a urinary proteomics biomarker panel consisting of 50 peptides, was applied to all datasets. The association of COV50 scoring with mortality was evaluated. Results In the ICU group, an increase in the COV50 score of one unit resulted in a 20% higher relative risk of death [adjusted HR 1.2 (95% CI 1.17–1.24)]. The same increase in COV50 in non-ICU patients resulted in a higher relative risk of 61% [adjusted HR 1.61 (95% CI 1.47–1.76)], consistent with adjusted meta-analytic HR estimate of 1.55 [95% CI 1.39–1.73]. The most notable and significant changes associated with future fatal events were reductions of specific collagen fragments, most of collagen alpha I (I). Conclusion The COV50 classifier is predictive of death in the absence of SARS-CoV-2 infection, suggesting that it detects pre-existing vulnerability. This prediction is mainly based on collagen fragments, possibly reflecting disturbances in the integrity of the extracellular matrix. These data may serve as a basis for proteomics-guided intervention aiming towards manipulating/ improving collagen turnover, thereby reducing the risk of death.

Published
2023
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4. A universal predictive and mechanistic urinary peptide signature in acute kidney injury

Author

Alexis Piedrafita, Justyna Siwy, Julie Klein, Amal Akkari, Ana Amaya-garrido, Alexandre Mebazaa, Anna Belen Sanz, Benjamin Breuil, Laura Montero Herrero, Bertrand Marcheix, François Depret, Lucie Fernandez, Elsa Tardif, Vincent Minville, Melinda Alves, Jochen Metzger, Kidney Attack Study Group, Julia Grossac, Harald Mischak, Alberto Ortiz, Stéphane Gazut, Joost P. Schanstra, Stanislas Faguer, Nicolas Mayeur, Audrey Casemayou, and François Labaste

Subjects
Acute kidney injury, Cardiac surgery, Intensive care unit, Urinary peptidomics, Prediction, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Abstract Background The delayed diagnosis of acute kidney injury (AKI) episodes and the lack of specificity of current single AKI biomarkers hamper its management. Urinary peptidome analysis may help to identify early molecular changes in AKI and grasp its complexity to identify potential targetable molecular pathways. Methods In derivation and validation cohorts totalizing 1170 major cardiac bypass surgery patients and in an external cohort of 1569 intensive care unit (ICU) patients, a peptide-based score predictive of AKI (7-day KDIGO classification) was developed, validated, and compared to the reference biomarker urinary NGAL and NephroCheck and clinical scores. Results A set of 204 urinary peptides derived from 48 proteins related to hemolysis, inflammation, immune cells trafficking, innate immunity, and cell growth and survival was identified and validated for the early discrimination (

Published
2022
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5. Prognosis and Personalized In Silico Prediction of Treatment Efficacy in Cardiovascular and Chronic Kidney Disease: A Proof-of-Concept Study

Author

Mayra Alejandra Jaimes Campos, Iván Andújar, Felix Keller, Gert Mayer, Peter Rossing, Jan A. Staessen, Christian Delles, Joachim Beige, Griet Glorieux, Andrew L. Clark, William Mullen, Joost P. Schanstra, Antonia Vlahou, Kasper Rossing, Karlheinz Peter, Alberto Ortiz, Archie Campbell, Frederik Persson, Agnieszka Latosinska, Harald Mischak, Justyna Siwy, and Joachim Jankowski

Subjects
cardiovascular events, coronary artery disease, heart failure, chronic kidney disease, personalized medicine, urinary biomarkers, Medicine, Pharmacy and materia medica, RS1-441
Abstract

(1) Background: Kidney and cardiovascular diseases are responsible for a large fraction of population morbidity and mortality. Early, targeted, personalized intervention represents the ideal approach to cope with this challenge. Proteomic/peptidomic changes are largely responsible for the onset and progression of these diseases and should hold information about the optimal means of treatment and prevention. (2) Methods: We investigated the prediction of renal or cardiovascular events using previously defined urinary peptidomic classifiers CKD273, HF2, and CAD160 in a cohort of 5585 subjects, in a retrospective study. (3) Results: We have demonstrated a highly significant prediction of events, with an HR of 2.59, 1.71, and 4.12 for HF, CAD, and CKD, respectively. We applied in silico treatment, implementing on each patient’s urinary profile changes to the classifiers corresponding to exactly defined peptide abundance changes, following commonly used interventions (MRA, SGLT2i, DPP4i, ARB, GLP1RA, olive oil, and exercise), as defined in previous studies. Applying the proteomic classifiers after the in silico treatment indicated the individual benefits of specific interventions on a personalized level. (4) Conclusions: The in silico evaluation may provide information on the future impact of specific drugs and interventions on endpoints, opening the door to a precision-based medicine approach. An investigation into the extent of the benefit of this approach in a prospective clinical trial is warranted.

Published
2023
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6. Ibrutinib does not prevent kidney fibrosis following acute and chronic injury

Author

Julie Belliere, Audrey Casemayou, Eloïse Colliou, Hélène El Hachem, Clément Kounde, Alexis Piedrafita, Guylène Feuillet, Joost P. Schanstra, and Stanislas Faguer

Subjects
Medicine, Science
Abstract

Abstract Recent studies suggested that ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor, developed for the treatment of chronic lymphocytic leukemia, may prevent NLRP3 inflammasome activation in macrophages, IL-1β secretion and subsequent development of inflammation and organ fibrosis. The role of NLRP3 has been underlined in the various causes of acute kidney injury (AKI), a pathology characterized by high morbimortality and risk of transition toward chronic kidney disease (CKD). We therefore hypothesized that the BTK-inhibitor ibrutinib could be a candidate drug for AKI treatment. Here, we observed in both an AKI model (glycerol-induced rhabdomyolysis) and a model of rapidly progressive kidney fibrosis (unilateral ureteral obstruction), that ibrutinib did not prevent inflammatory cell recruitment in the kidney and fibrosis. Moreover, ibrutinib pre-exposure led to high mortality rate owing to severer rhabdomyolysis and AKI. In vitro, ibrutinib potentiated or had no effect on the secretion of IL-1β by monocytes exposed to uromodulin or myoglobin, two danger-associated molecule patterns proteins involved in the AKI to CKD transition. According to these results, ibrutinib should not be considered a candidate drug for patients developing AKI.

Published
2021
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7. PRYNT: a tool for prioritization of disease candidates from proteomics data using a combination of shortest-path and random walk algorithms

Author

Franck Boizard, Bénédicte Buffin-Meyer, Julien Aligon, Olivier Teste, Joost P. Schanstra, and Julie Klein

Subjects
Medicine, Science
Abstract

Abstract The urinary proteome is a promising pool of biomarkers of kidney disease. However, the protein changes observed in urine only partially reflect the deregulated mechanisms within kidney tissue. In order to improve on the mechanistic insight based on the urinary protein changes, we developed a new prioritization strategy called PRYNT (PRioritization bY protein NeTwork) that employs a combination of two closeness-based algorithms, shortest-path and random walk, and a contextualized protein–protein interaction (PPI) network, mainly based on clique consolidation of STRING network. To assess the performance of our approach, we evaluated both precision and specificity of PRYNT in prioritizing kidney disease candidates. Using four urinary proteome datasets, PRYNT prioritization performed better than other prioritization methods and tools available in the literature. Moreover, PRYNT performed to a similar, but complementary, extent compared to the upstream regulator analysis from the commercial Ingenuity Pathway Analysis software. In conclusion, PRYNT appears to be a valuable freely accessible tool to predict key proteins indirectly from urinary proteome data. In the future, PRYNT approach could be applied to other biofluids, molecular traits and diseases. The source code is freely available on GitHub at: https://github.com/Boizard/PRYNT and has been integrated as an interactive web apps to improved accessibility ( https://github.com/Boizard/PRYNT/tree/master/AppPRYNT ).

Published
2021
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8. Comparison of the amniotic fluid and fetal urine peptidome for biomarker discovery in renal developmental disease

Author

Camille Fédou, Benjamin Breuil, Igor Golovko, Stéphane Decramer, Pedro Magalhães, Françoise Muller, Sophie Dreux, Petra Zürbig, Julie Klein, Joost P. Schanstra, and Bénédicte Buffin-Meyer

Subjects
Medicine, Science
Abstract

Abstract Production of amniotic fluid (AF) is view as predominately driven by excretion of fetal urine (FU). However, the origin of AF peptides, often considered as potential biomarkers of developmental diseases, has never been investigated. Here, we evaluated the FU origin of AF peptides and if the AF peptide content can be used as a surrogate of FU. The abundance of endogenous peptides was analyzed by capillary electrophoresis coupled to mass spectrometry in 216 AF and 64 FU samples. A total of 2668 and 3257 peptides was found in AF and FU respectively. The AF peptidome largely overlapped with the FU peptidome, ranging from 54% in the second pregnancy trimester to 65% in the third trimester. Examination of a subset of 16 paired AF and FU samples revealed that 67 peptides displayed a significant positively correlated abundance in AF and FU, strongly suggesting that their presence in AF was directly associated to FU excretion. As proof-of-concept we showed that measuring the AF abundance of these 67 peptides of FU origin allowed prediction of postnatal renal survival in fetuses with posterior urethral valves. These results demonstrate that the AF peptidome can be considered as a good surrogate of the FU peptidome.

Published
2020
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9. Blockade of the kallikrein-kinin system reduces endothelial complement activation in vascular inflammationResearch in context

Author

Ingrid Lopatko Fagerström, Anne-lie Ståhl, Maria Mossberg, Ramesh Tati, Ann-Charlotte Kristoffersson, Robin Kahn, Jean-Loup Bascands, Julie Klein, Joost P. Schanstra, Mårten Segelmark, and Diana Karpman

Subjects
Medicine, Medicine (General), R5-920
Abstract

Background: The complement and kallikrein-kinin systems (KKS) are activated during vascular inflammation. The aim of this study was to investigate if blockade of the KKS can affect complement activation on the endothelium during inflammation. Methods: Complement deposition on endothelial microvesicles was assayed in vasculitis patient plasma samples and controls. Plasma was perfused over glomerular endothelial cells and complement deposition assayed by flow cytometry. The effect of the kinin system was assessed using kinin receptor antagonists and C1-inhibitor. The in vivo effect was assessed in kidney sections from mice with nephrotoxic serum-induced glomerulonephritis treated with a kinin receptor antagonist. Findings: Vasculitis patient plasma had significantly more C3- and C9-positive endothelial microvesicles than controls. Perfusion of patient acute-phase plasma samples over glomerular endothelial cells induced the release of significantly more complement-positive microvesicles, in comparison to remission or control plasma. Complement activation on endothelial microvesicles was reduced by kinin B1- and B2-receptor antagonists or by C1-inhibitor (the main inhibitor of the classical pathway and the KKS). Likewise, perfusion of glomerular endothelial cells with C1-inhibitor-depleted plasma induced the release of complement-positive microvesicles, which was significantly reduced by kinin-receptor antagonists or C1-inhibitor. Mice with nephrotoxic serum-induced glomerulonephritis exhibited significantly reduced glomerular C3 deposition when treated with a B1-receptor antagonist. Interpretation: Excessive complement deposition on the endothelium will promote endothelial injury and the release of endothelial microvesicles. This study demonstrates that blockade of the KKS can reduce complement activation and thereby the inflammatory response on the endothelium. Funding: Full details are provided in the Acknowledgements/Funding section. Keywords: Vasculitis, Endothelial microvesicles, Complement, Kinin, Kidney, Mouse

Published
2019
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10. Publisher Correction to: A universal predictive and mechanistic urinary peptide signature in acute kidney injury

Author

Alexis Piedrafita, Justyna Siwy, Julie Klein, Amal Akkari, Ana Amaya-garrido, Alexandre Mebazaa, Anna Belen Sanz, Benjamin Breuil, Laura Montero Herrero, Bertrand Marcheix, François Depret, Lucie Fernandez, Elsa Tardif, Vincent Minville, Melinda Alves, Jochen Metzger, Kidney Attack Study Group, Julia Grossac, Harald Mischak, Alberto Ortiz, Stéphane Gazut, Joost P. Schanstra, and Stanislas Faguer

Subjects
Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Published
2022
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11. Proteomics based identification of KDM5 histone demethylases associated with cardiovascular diseaseResearch in context

Author

Marika Mokou, Julie Klein, Manousos Makridakis, Vasiliki Bitsika, Jean-Loup Bascands, Jean Sebastien Saulnier-Blache, William Mullen, Michael Sacherer, Jerome Zoidakis, Burkert Pieske, Harald Mischak, Maria G. Roubelakis, Joost P. Schanstra, and Antonia Vlahou

Subjects
Medicine, Medicine (General), R5-920
Abstract

Background: The increased prevalence of cardiovascular disease (CVD) indicates a demand for novel therapeutic approaches. Proteome analysis of vascular tissues from animal models and humans with CVD could lead to the identification of novel druggable targets. Methods: LC-MS/MS analysis of thoracic aortas from three mouse models of non-diabetic and diabetic (streptozotocin (STZ)-induced) atherosclerosis followed by bioinformatics/pathway analysis was performed. Selected findings were confirmed by proteomics analysis of human vessels from patients with CVD as well as in vitro studies (migration, proliferation, angiogenesis assays) using endothelial (HUVEC) cells. Findings: Comparative tissue proteomics of low density lipoprotein receptor deficient (Ldlr−/−) and diabetic Ldlr−/− (Ldlr−/−STZ) with wild type (WT) animals led to the identification of 284 differentially expressed proteins in both models. Among them, 177 proteins were also differentially expressed in diabetic apolipoprotein E deficient (ApoE−/−STZ) mice, suggesting expression changes associated with atherosclerosis independent of the model used. These proteins recapitulated the hallmarks of atherosclerosis. Comparison of these findings with differentially expressed proteins in human vessels with CVD enabled shortlisting of six commonly dysregulated proteins. Among them, lysine-specific demethylase 5D (KDM5D) exhibited pronounced overexpression accompanied by a reduction in the protein levels of its substrate, the trimethylated lysine 4 of histone H3 (H3K4me3), in patients with CVD. Functional interference studies applying a KDM5 inhibitor on HUVEC reduced cell proliferation, migration and tube-forming ability in vitro. Interpretation: This high-throughput proteomics strategy identified KDM5 histone demethylases being potentially involved in CVD, possibly by affecting H3K4 methylation. Fund: [SysVasc, HEALTH-2013 603288], [ERA-CVD PROACT: ANR-17-ECVD-0006, 01KL1805], [FRM, DEQ20170336759]. Keywords: Cardiovascular disease, Atherosclerosis, Diabetes, Proteomics, KDM5, H3K4

Published
2019
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12. Plasma proteomic analysis reveals altered protein abundances in cardiovascular disease

Author

Vasiliki Lygirou, Agnieszka Latosinska, Manousos Makridakis, William Mullen, Christian Delles, Joost P. Schanstra, Jerome Zoidakis, Burkert Pieske, Harald Mischak, and Antonia Vlahou

Subjects
Cardiovascular disease, Proteomics, Plasma, LC–MS/MS, Proteomic dataset, Biomarker, Medicine
Abstract

Abstract Background Cardiovascular disease (CVD) describes the pathological conditions of the heart and blood vessels. Despite the large number of studies on CVD and its etiology, its key modulators remain largely unknown. To this end, we performed a comprehensive proteomic analysis of blood plasma, with the scope to identify disease-associated changes after placing them in the context of existing knowledge, and generate a well characterized dataset for further use in CVD multi-omics integrative analysis. Methods LC–MS/MS was employed to analyze plasma from 32 subjects (19 cases of various CVD phenotypes and 13 controls) in two steps: discovery (13 cases and 8 controls) and test (6 cases and 5 controls) set analysis. Following label-free quantification, the detected proteins were correlated to existing plasma proteomics datasets (plasma proteome database; PPD) and functionally annotated (Cytoscape, Ingenuity Pathway Analysis). Differential expression was defined based on identification confidence (≥ 2 peptides per protein), statistical significance (Mann–Whitney p value ≤ 0.05) and a minimum of twofold change. Results Peptides detected in at least 50% of samples per group were considered, resulting in a total of 3796 identified proteins (838 proteins based on ≥ 2 peptides). Pathway annotation confirmed the functional relevance of the findings (representation of complement cascade, fibrin clot formation, platelet degranulation, etc.). Correlation of the relative abundance of the proteins identified in the discovery set with their reported concentrations in the PPD was significant, confirming the validity of the quantification method. The discovery set analysis revealed 100 differentially expressed proteins between cases and controls, 39 of which were verified (≥ twofold change) in the test set. These included proteins already studied in the context of CVD (such as apolipoprotein B, alpha-2-macroglobulin), as well as novel findings (such as low density lipoprotein receptor related protein 2 [LRP2], protein SZT2) for which a mechanism of action is suggested. Conclusions This proteomic study provides a comprehensive dataset to be used for integrative and functional studies in the field. The observed protein changes reflect known CVD-related processes (e.g. lipid uptake, inflammation) but also novel hypotheses for further investigation including a potential pleiotropic role of LPR2 but also links of SZT2 to CVD.

Published
2018
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13. Collagen-Derived Peptides in CKD: A Link to Fibrosis

Author

Emmanouil Mavrogeorgis, Harald Mischak, Agnieszka Latosinska, Antonia Vlahou, Joost P. Schanstra, Justyna Siwy, Vera Jankowski, Joachim Beige, and Joachim Jankowski

Subjects
CE-MS, chronic kidney disease, collagen alpha-1(I) chain, fibrosis, urine, Medicine
Abstract

Collagen is a major component of the extracellular matrix (ECM) and has an imminent role in fibrosis, in, among others, chronic kidney disease (CKD). Collagen alpha-1(I) (col1a1) is the most abundant collagen type and has previously been underlined for its contribution to the disease phenotype. Here, we examined 5000 urinary peptidomic datasets randomly selected from healthy participants or patients with CKD to identify urinary col1a1 fragments and study their abundance, position in the main protein, as well as their correlation with renal function. We identified 707 col1a1 peptides that differed in their amino acid sequence and/or post-translational modifications (hydroxyprolines). Well-correlated peptides with the same amino acid sequence, but a different number of hydroxyprolines, were combined into a final list of 503 peptides. These 503 col1a1 peptides covered 69% of the full col1a1 sequence. Sixty-three col1a1 peptides were significantly and highly positively associated (rho > +0.3) with the estimated glomerular filtration rate (eGFR), while only six peptides showed a significant and strong, negative association (rho < −0.3). A similar tendency was observed for col1a1 peptides associated with ageing, where the abundance of most col1a1 peptides decreased with increasing age. Collectively the results show a strong association between collagen peptides and loss of kidney function and suggest that fibrosis, potentially also of other organs, may be the main consequence of an attenuation of collagen degradation, and not increased synthesis.

Published
2021
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14. Prediction of Chronic Kidney Disease Stage 3 by CKD273, a Urinary Proteomic Biomarker

Author

Claudia Pontillo, Zhen-Yu Zhang, Joost P. Schanstra, Lotte Jacobs, Petra Zürbig, Lutgarde Thijs, Adela Ramírez-Torres, Hiddo J.L. Heerspink, Morten Lindhardt, Ronald Klein, Trevor Orchard, Massimo Porta, Rudolf W. Bilous, Nishi Charturvedi, Peter Rossing, Antonia Vlahou, Eva Schepers, Griet Glorieux, William Mullen, Christian Delles, Peter Verhamme, Raymond Vanholder, Jan A. Staessen, Harald Mischak, and Joachim Jankowski

Subjects
biomarker, chronic kidney disease, clinical science, glomerular filtration rate, peptidomics, proteomics, Diseases of the genitourinary system. Urology, RC870-923
Abstract

CKD273 is a urinary biomarker, which in advanced chronic kidney disease predicts further deterioration. We investigated whether CKD273 can also predict a decline of estimated glomerular filtration rate (eGFR) to

Published
2017
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15. Molecular Changes in Tissue Proteome during Prostate Cancer Development: Proof-of-Principle Investigation

Author

Agnieszka Latosinska, Katarina Davalieva, Manousos Makridakis, William Mullen, Joost P. Schanstra, Antonia Vlahou, Harald Mischak, and Maria Frantzi

Subjects
drug target, personalized medicine, prostate cancer, proteomics, tissue, Medicine (General), R5-920
Abstract

(1) Background: Prostate cancer (PCa) is characterized by high heterogeneity. The aim of this study was to investigate molecular alterations underlying PCa development based on proteomics data. (2) Methods: Liquid chromatography coupled to tandem mass spectrometry was conducted for 22 fresh-frozen tissue specimens from patients with benign prostatic hyperplasia (BPH, n = 5) and PCa (n = 17). Mann Whitney test was used to define significant differences between the two groups. Association of protein abundance with PCa progression was evaluated using Spearman correlation, followed by verification through investigating the Prostate Cancer Transcriptome Atlas. Functional enrichment and interactome analysis were carried out using Metascape and String. (3) Results: Proteomics analysis identified 1433 proteins, including 145 proteins as differentially abundant between patients with PCa and BPH. In silico analysis revealed alterations in several pathways and hallmarks implicated in metabolism and signalling, represented by 67 proteins. Among the latter, 21 proteins were correlated with PCa progression at both the protein and mRNA levels. Interactome analysis of these 21 proteins predicted interactions between Myc proto-oncogene (MYC) targets, protein processing in the endoplasmic reticulum, and oxidative phosphorylation, with MYC targets having a central role. (4) Conclusions: Tissue proteomics allowed for characterization of proteins and pathways consistently affected during PCa development. Further validation of these findings is required.

Published
2020
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16. Omics Derived Biomarkers and Novel Drug Targets for Improved Intervention in Advanced Prostate Cancer

Author

Maria Frantzi, Marie C. Hupe, Axel S. Merseburger, Joost P. Schanstra, Harald Mischak, and Agnieszka Latosinska

Subjects
biomarkers, drug targets, omics, prostate cancer, Medicine (General), R5-920
Abstract

Prostate cancer (PCa) is one of the most frequently diagnosed malignancies, and the fifth leading cause of cancer related mortality in men. For advanced PCa, radical prostatectomy, radiotherapy, and/or long-term androgen deprivation therapy are the recommended treatment options. However, subsequent progression to metastatic disease after initial therapy results in low 5-year survival rates (29%). Omics technologies enable the acquisition of high-resolution large datasets that can provide insights into molecular mechanisms underlying PCa pathology. For the purpose of this article, a systematic literature search was conducted through the Web of Science Database to critically evaluate recent omics-driven studies that were performed towards: (a) Biomarker development and (b) characterization of novel molecular-based therapeutic targets. The results indicate that multiple omics-based biomarkers with prognostic and predictive value have been validated in the context of PCa, with several of those being also available for commercial use. At the same time, omics-driven potential drug targets have been investigated in pre-clinical settings and even in clinical trials, holding the promise for improved clinical management of advanced PCa, as part of personalized medicine pipelines.

Published
2020
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17. Machine Learning-Based Urine Peptidome Analysis to Predict and Understand Mechanisms of Progression to Kidney Failure

Author

Ziad A. Massy, Oriane Lambert, Marie Metzger, Mohammed Sedki, Adeline Chaubet, Benjamin Breuil, Acil Jaafar, Ivan Tack, Thao Nguyen-Khoa, Melinda Alves, Justyna Siwy, Harald Mischak, Francis Verbeke, Griet Glorieux, Yves-Edouard Herpe, Joost P. Schanstra, Bénédicte Stengel, Julie Klein, Natalia ALENCAR DE PINHO, Carole AYAV, Dorothée CANNET, Christian COMBE, Jean-François DELEUZE, Denis FOUQUE, Luc FRIMAT, Yves-Edouard HERPE, Christian JACQUELINET, Maurice LAVILLE, Sophie LIABEUF, Ziad A. MASSY, Christophe PASCAL, Bruce ROBINSON, Roberto PECOITS-FILHO, Joost SCHANSTRA, Bénédicte STENGEL, Céline LANGE, Marie METZGER, and Elodie SPEYER

Subjects
Nephrology
Published
2023
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18. Systems biology combining human- and animal-data miRNA and mRNA data identifies new targets in ureteropelvic junction obstruction.

Author

Theofilos Papadopoulos, Audrey Casemayou, Eric Neau, Benjamin Breuil, Cécile Caubet, Denis Calise, Barbara A. Thornhill, Magdalena Bachvarova, Julie Belliere, Robert L. Chevalier, Panagiotis Moulos, Dimcho Bachvarov, Benedicte Buffin-Meyer, Stéphane Decramer, Françoise Conte Auriol, Jean-Loup Bascands, Joost P. Schanstra, and Julie Klein 0002

Published
2017
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19. Uniform Manifold Approximation and Projection-based Assessment of Chronic Kidney Disease Aetiologies based on Urinary Peptidomics

Author

Emmanouil Mavrogeorgis, Tianlin He, Harald Mischak, Agnieszka Latosinska, antonia vlahou, Joost P Schanstra, Lorenzo Catanese, Kerstin Amann, Tobias B Huber, Joachim Beige, Harald Rupprecht, and Justyna Siwy

Abstract

Background The impact of artificial intelligence combined with advanced techniques is ever-increasing in the biomedical field appearing promising, among others, in chronic kidney disease (CKD) diagnosis. However, existing models are often single-aetiology specific. Proposed here is a pipeline for the development of single models able to distinguish and spatially visualize multiple CKD aetiologies. Methods Acquired were from the Human Urinary Proteome Database the urinary peptide data of 1850 healthy control (HC) and CKD (diabetic kidney disease-DKD, IgA nephropathy-IgAN, vasculitis) participants. The uniform manifold approximation and projection (UMAP) method was coupled to a support vector machine (SVM) algorithm. Binary (DKD, HC) and multiclass (DKD, HC, IgAN, vasculitis) classifications were performed, including or skipping the UMAP step. Last, the pipeline was compared to the current state-of-the-art single-aetiology CKD urinary models. Findings In an independent test set, the developed models (including the UMAP step) achieved 90.35% and 70.13% overall predictive accuracies, respectively, for the binary and the multiclass classifications (96.14% and 85.06%, skipping the UMAP step). Overall, the HC class was distinguished with the highest accuracy. The different classes displayed a tendency to form distinct clusters in the 3D-space based on their disease state. Interpretation Urinary peptide data appear to potentially be an effective basis for CKD aetiology differentiation. The UMAP step may provide a unique visualization advantage capturing the relevant molecular (patho)physiology. Further studies are warranted to validate the pipelines clinical potential in the presented as well as other CKD aetiologies or even other diseases.

Published
2023
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20. The COV50 classifier predicts frailty and future death, independent from SARS-CoV-2 infection

Author

Felix Keller, Joachim Beige, Justyna Siwy, Alexandre Mebazaa, Dewei An, Harald Mischak, Joost P. Schanstra, Marika Mokou, Paul Perco, Jan A. Staessen, Antonia Vlahou, and Agnieszka Latosinska

Abstract

SummaryCOV50, a urinary proteomic classifier, predicts disease progression and death from SARS-CoV-2 at early stage, suggesting it might predict pre-established vulnerability. This study investigated the value of COV50 in predicting non-COVID-19 associated death. Urinary proteomic data were extracted from the Human Urinary Proteome Database. In the ICU group (n=1719), an increase in the COV50 score of one unit resulted in a 20% higher relative risk of death (adj. HR 1·2 [95% CI 1·17-1·24]). The same increase in COV50 in non-ICU patients (n=7474) resulted in a higher relative risk of 61% (adj. HR 1·61 [95% CI 1·47-1·76]), in line with adjusted meta-analytic HR estimate of 1·55. A higher COV50 scoring was observed in frail patients (p

Published
2023
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22. Associations of urinary polymeric immunoglobulin receptor peptides in the context of cardio-renal syndrome

Author

Vera Jankowski, Tianlin He, Justyna Siwy, Harald Mischak, Joost P. Schanstra, William Mullen, Petra Zürbig, Jochen Metzger, Mosaiques Diagnostics GmbH [Hanovre, Allemagne], Universitätsklinikum RWTH Aachen - University Hospital Aachen [Aachen, Germany] (UKA), RWTH Aachen University, University of Glasgow, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées, This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant number 764474. Joost P. Schanstra was supported by the 'Fondation pour la Recherche Médicale' (grant number DEQ20170336759)., Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), and Bodescot, Myriam

Subjects
Proteomics, Adult, Male, Proteases, Secretory component, Urinary system, Cardiology, lcsh:Medicine, Immunoglobulins, Peptide, Context (language use), 030204 cardiovascular system & hematology, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Article, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Humans, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], lcsh:Science, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], 030304 developmental biology, Aged, chemistry.chemical_classification, 0303 health sciences, Multidisciplinary, biology, Cardio-Renal Syndrome, lcsh:R, Receptors, Polymeric Immunoglobulin, Middle Aged, Molecular biology, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Secretory Component, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, chemistry, Nephrology, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Proteome, biology.protein, lcsh:Q, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Antibody, Polymeric immunoglobulin receptor, Peptides, Biomarkers, Glomerular Filtration Rate
Abstract

The polymeric immunoglobulin receptor (pIgR) transports immunoglobulins from the basolateral to the apical surface of epithelial cells. PIgR was recently shown to be associated with kidney dysfunction. The immune defense is initiated at the apical surface of epithelial cells where the N-terminal domain of pIgR, termed secretory component (SC), is proteolytically cleaved and released either unbound (free SC) or bound to immunoglobulins. The aim of our study was to evaluate the association of pIgR peptides with the cardio-renal syndrome in a large cohort and to obtain information on how the SC is released. We investigated urinary peptides of 2964 individuals available in the Human Urine Proteome Database generated using capillary electrophoresis coupled to mass spectrometry. The mean amplitude of 23 different pIgR peptides correlated negatively with the estimated glomerular filtration rate (eGFR, rho = −0.309, p

Published
2020
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23. Haploinsufficiency of the mouse Tshz3 gene leads to kidney dysfunction

Author

Laurent Fasano, Colette Denis, Guylène Feuillet, Andy Saurin, Ahmed Fatmi, Thien Phong Vu Manh, Petra Zürbig, Joost P. Schanstra, Irene Sanchez-Martin, Xavier Caubit, Fabrice Richard, Pedro Magalhães, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), Hannover Medical School [Hannover] (MHH), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Mosaiques Diagnostics GmbH, Fasano, Laurent, Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 642937, ANR-17-CE16-0030-01 'TSHZ3inASD', Aix Marseille Univ, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Marseille, France., Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0303 health sciences, Kidney, Stromal cell, urogenital system, Urinary system, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, Wild type, Biology, Molecular biology, Phenotype, [SHS]Humanities and Social Sciences, Transcriptome, [SDV] Life Sciences [q-bio], 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, medicine, Haploinsufficiency, Renal pelvis, 030304 developmental biology
Abstract

Renal tract defects and autism spectrum disorder (ASD) deficits represent the phenotypic core of the 19q12 deletion syndrome caused by the loss of one copy of the TSHZ3 gene. While a proportion of Tshz3 heterozygous (Tshz3+/lacZ) mice display ureteral defects, no kidney defects have been reported in these mice. The purpose of this study was to characterize the expression of Tshz3 in adult kidney as well as the renal physiological consequences of embryonic haploinsufficiency of Tshz3 by analyzing the morphology and function of Tshz3 heterozygous adult kidney. Here, we described Tshz3 expression in the smooth muscle and stromal cells lining the renal pelvis, the papilla and glomerular endothelial cells (GEnCs) of the adult kidney. Histological analysis showed that Tshz3+/lacZ adult kidney had an average of 29% fewer glomeruli than wild type kidney. Transmission electron microscopy (TEM) of Tshz3+/lacZ glomeruli revealed ultrastructural defects. Compared to wild type, Tshz3+/lacZ mice showed no difference in their urine parameters but lower blood urea, phosphates, magnesium and potassium at 2 months of age. At the molecular level, transcriptome analysis identified differentially expressed genes related to inflammatory processes in Tshz3+/lacZ compare to wild type (WT; control) adult kidneys. Lastly, analysis of the urinary peptidome revealed 33 peptides associated with Tshz3+/lacZ adult mice. These results provide the first evidence that in the mouse Tshz3 haploinsufficiency leads to cellular, molecular and functional abnormalities in the adult mouse kidney.

Published
2021

24. Proteomic analysis of mouse kidney tissue associates peroxisomal dysfunction with early diabetic kidney disease

Author

Aggeliki Tserga, Jerome Zoidakis, Irene Theochari, Harikleia Gakiopoulou, Joost P. Schanstra, Rafael Stroggilos, Manousos Makridakis, Jean Sébastien Saulnier-Blache, Despoina Pouloudi, Harald Mischak, and Antonia Vlahou

Subjects
Pathogenesis, Kidney, medicine.anatomical_structure, Downregulation and upregulation, Aminoacid metabolism, Proteome, medicine, Cancer research, ACOX1, Lipid metabolism, Peroxisome, Biology
Abstract

BackgroundThe absence of efficient inhibitors for DKD progression reflects the gaps in our understanding of DKD molecular pathogenesis. A comprehensive proteomic analysis was performed on glomeruli and kidney cortex of diabetic mice with subsequent validation of findings in human biopsies and - omics datasets aiming to better understand the underlying molecular biology of early DKD development and progression.MethodsLC–MS/MS was employed to analyze the kidney proteome of DKD mouse models: Glomeruli of Ins2Akita mice 2 month and 4 month old, and cortex of db/db mice 6 month old. Following label-free quantification, the abundance of detected proteins were correlated with existing kidney datasets and functionally annotated. Tissue sections from 16 DKD patients were analyzed by IHC.ResultsPathway analysis of differentially expressed proteins in the early and late DKD versus controls predicted dysregulation in DKD hallmarks (such as peroxisomal lipid metabolism, β-oxidation and TCA cycle) supporting the functional relevance of the findings. Comparing the observed protein changes in early and late DKD, consistent upregulation of 21 and downregulation of 18 proteins was detected. Among these were downregulated peroxisomal proteins such as NUDT19, ACOX1, and AMACR and upregulated mitochondrial proteins related to aminoacid metabolism including GLS, GLDC, and GCAT. Several of these changes were also observed in the kidney cortex proteome of db/db mice. IHC of human kidney further confirmed the differential expression of NUDT19, AGPS, AMACR and CAT proteins in DKD.ConclusionsOur study shows an extensive differential expression of peroxisomal proteins in the early stages of DKD that persists regardless of the disease severity. These proteins therefore represent potential markers of early DKD pathogenesis. Collectively, essential pathways associated with peroxisomes such as lipid β-oxidation, plasmalogen synthesis, aminoacid metabolism and response to oxidative stress are downregulated in early DKD, providing new perspectives and potential markers of diabetic kidney dysfunction.

Published
2021
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25. Hepatocyte nuclear factor-1β shapes the energetic homeostasis of kidney tubule cells

Author

Alexis Piedrafita, Stanislas Faguer, Benjamin Breuil, Stéphane Decramer, Dominique Chauveau, Joost P. Schanstra, Myriam Malet-Martino, Stéphane Balayssac, Jean-Sébastien Saulnier-Blache, Jason S. Iacovoni, Alexandre Lucas, Audrey Casemayou, Institut National de la Santé et de la Recherche Médicale - INSERM, Interactions moléculaires et réactivité chimique et photochimique (IMRCP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Service de Néphrologie et Immunopathologie Clinique, Centre Hospitalier Universitaire de Toulouse, PRES Université de Toulouse, CHU Toulouse [Toulouse], Institut des Maladies Métaboliques et Casdiovasculaires (UPS/Inserm U1297 - I2MC), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT), Centre de Référence du Sud Ouest des Maladies Rénales Rares, Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Fédération de Recherche Fluides, Energie, Réacteurs, Matériaux et Transferts (FERMAT), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), BIBAC - Chimie analytique et interactions biomolécules - matière molle biomimétique (BIBAC), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie de Toulouse (ICT), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées, Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), and Saulnier-Blache, Jean Sébastien

Subjects
Choline kinase, Cell Survival, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, HNF-1β, Biochemistry, Cell Line, Kidney Tubules, Proximal, 03 medical and health sciences, Gene Knockout Techniques, Mice, 0302 clinical medicine, Genetics, medicine, [CHIM]Chemical Sciences, Animals, Homeostasis, Humans, Glycolysis, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Cell Proliferation, Hepatocyte Nuclear Factor 1-beta, 0303 health sciences, Kidney, kidney tubule, Chemistry, hypoxia, metabolism, Epithelial Cells, Metabolism, Acute Kidney Injury, Cell Hypoxia, Cell biology, Citric acid cycle, [SDV] Life Sciences [q-bio], Hepatocyte nuclear factors, Cytosol, medicine.anatomical_structure, Gene Expression Regulation, Metabolome, CRISPR-Cas Systems, Transcriptome, Gene Deletion, Biotechnology, Signal Transduction
Abstract

International audience; Energetic metabolism controls key steps of kidney development, homeostasis, and epithelial repair following acute kidney injury (AKI). Hepatocyte nuclear factor-1β (HNF-1β) is a master transcription factor that controls mitochondrial function in proximal tubule (PT) cells. Patients with HNF1B pathogenic variant display a wide range of kidney developmental abnormalities and progressive kidney fibrosis. Characterizing the metabolic changes in PT cells with HNF-1β deficiency may help to identify new targetable molecular hubs involved in HNF1B-related kidney phenotypes and AKI. Here, we combined 1 H-NMR-based metabolomic analysis in a murine PT cell line with CrispR/Cas9-induced Hnf1b invalidation (Hnf1b-/- ), clustering analysis, targeted metabolic assays, and datamining of published RNA-seq and ChIP-seq dataset to identify the role of HNF-1β in metabolism. Hnf1b-/- cells grown in normoxic conditions display intracellular ATP depletion, increased cytosolic lactate concentration, increased lipid droplet content, failure to use pyruvate for energetic purposes, increased levels of tricarboxylic acid (TCA) cycle intermediates and oxidized glutathione, and a reduction of TCA cycle byproducts, all features consistent with mitochondrial dysfunction and an irreversible switch toward glycolysis. Unsupervised clustering analysis showed that Hnf1b-/- cells mimic a hypoxic signature and that they cannot furthermore increase glycolysis-dependent energetic supply during hypoxic challenge. Metabolome analysis also showed alteration of phospholipid biosynthesis in Hnf1b-/- cells leading to the identification of Chka, the gene coding for choline kinase α, as a new putative target of HNF-1β. HNF-1β shapes the energetic metabolism of PT cells and HNF1B deficiency in patients could lead to a hypoxia-like metabolic state precluding further adaptation to ATP depletion following AKI.

Published
2021
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26. Haploinsufficiency of the mouse Tshz3 gene leads to kidney defects

Author

Irene Sanchez-Martin, Pedro Magalhães, Parisa Ranjzad, Ahmed Fatmi, Fabrice Richard, Thien Phong Vu Manh, Andrew J Saurin, Guylène Feuillet, Colette Denis, Adrian S Woolf, Joost P Schanstra, Petra Zürbig, Xavier Caubit, Laurent Fasano, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), Mosaiques Diagnostics GmbH [Hannover, Germany], Mosaiques Diagnostics and Therapeutics AG [Hannover, Germany], Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Maladies Métaboliques et Casdiovasculaires (UPS/Inserm U1297 - I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées, European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 642937, ANR-17-CE16-0030-01 'TSHZ3inASD', Medical Research Council project grant (MR/T016809/1), Kids Kidney Research/Kidney Research UK project grant (2010), ANR-17-CE16-0030,TSHZ3inASD,Rôle de TSHZ3 dans le développement et la fonction de systèmes neuronaux impliqués dans les troubles du spectre autistique(2017), Fasano, Laurent, Rôle de TSHZ3 dans le développement et la fonction de systèmes neuronaux impliqués dans les troubles du spectre autistique - - TSHZ3inASD2017 - ANR-17-CE16-0030 - AAPG2017 - VALID, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Toulouse (UT)

Subjects
[SDV.GEN]Life Sciences [q-bio]/Genetics, urogenital system, Autism Spectrum Disorder, Endothelial Cells, General Medicine, [SDV.GEN] Life Sciences [q-bio]/Genetics, Haploinsufficiency, Kidney, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Mice, Genetics, Animals, Kidney Diseases, Ureter, Molecular Biology, Genetics (clinical), Transcription Factors
Abstract

Renal tract defects and autism spectrum disorder (ASD) deficits represent the phenotypic core of the 19q12 deletion syndrome caused by the loss of one copy of the TSHZ3 gene. Although a proportion of Tshz3 heterozygous (Tshz3+/lacZ) mice display ureteral defects, no kidney defects have been reported in these mice. The purpose of this study was to characterize the expression of Tshz3 in adult kidney as well as the renal consequences of embryonic haploinsufficiency of Tshz3 by analyzing the morphology and function of Tshz3 heterozygous adult kidney. Here, we described Tshz3 expression in the smooth muscle and stromal cells lining the renal pelvis, the papilla and glomerular endothelial cells (GEnCs) of the adult kidney as well as in the proximal nephron tubules in neonatal mice. Histological analysis showed that Tshz3+/lacZ adult kidney had an average of 29% fewer glomeruli than wild-type kidney. Transmission electron microscopy of Tshz3+/lacZ glomeruli revealed a reduced thickness of the glomerular basement membrane and a larger foot process width. Compared to wild type, Tshz3+/lacZ mice showed lower blood urea, phosphates, magnesium and potassium at 2 months of age. At the molecular level, transcriptome analysis identified differentially expressed genes related to inflammatory processes in Tshz3+/lacZ compare to wild-type (control) adult kidneys. Lastly, analysis of the urinary peptidome revealed 33 peptides associated with Tshz3+/lacZ adult mice. These results provide the first evidence that in the mouse Tshz3 haploinsufficiency leads to cellular, molecular and functional abnormalities in the adult mouse kidney.

Published
2021
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27. Metabolic and cardiovascular adaptations to an 8-wk lifestyle weight loss intervention in younger and older obese men

Author

Dominique Langin, Marie-Adeline Marques, Cédric Dray, Sylvie Caspar-Bauguil, Dominique Larrouy, Sophie Bonnel, Philippe Valet, Cécile Vindis, Nathalie Viguerie, Veronika Šrámková, Virginie Bourlier, Isabelle Harant, Laurent O. Martinez, Cedric Moro, Thibaut Duparc, Claire Thalamas, Joost P. Schanstra, Jean-Sébastien Saulnier-Blache, Emilie Montastier, Nabila Moussaoui, Julie Vion, Institut des Maladies Métaboliques et Casdiovasculaires (UPS/Inserm U1297 - I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Charles University [Prague] (CU), Franco-czech Laboratory for clinical research on obesity, Charles University [Prague] (CU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Endocrinologie, maladies métaboliques et nutrition [CHU Toulouse], Pôle Cardiovasculaire et Métabolique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre d'investigation clinique de Toulouse (CIC 1436), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), Saulnier-Blache, Jean Sébastien, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, CHU Toulouse [Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Mégard, Roxane

Subjects
Gerontology, Adult, Male, medicine.medical_specialty, Physiology, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Calorie restriction, 030209 endocrinology & metabolism, Physical exercise, 030204 cardiovascular system & hematology, Cardiovascular System, 03 medical and health sciences, 0302 clinical medicine, Weight loss, physical exercise, Physiology (medical), Internal medicine, Intervention (counseling), cardiometabolic risk, Obesity management, medicine, Humans, Obesity, Life Style, Aged, 2. Zero hunger, Cardiometabolic risk, business.industry, Public health, aging, Age Factors, calorie restriction, Middle Aged, medicine.disease, Adaptation, Physiological, 3. Good health, [SDV] Life Sciences [q-bio], Weight Reduction Programs, Body Composition, medicine.symptom, business
Abstract

International audience; The number of older obese adults is increasing worldwide. Whether obese adults show similar health benefits in response to lifestyle interventions at different ages is unknown. The study enrolled 25 obese men (body mass index: 31-39 kg/m2) in two arms according to age (30-40 and 60-70 yr old). Participants underwent an 8-wk intervention with moderate calorie restriction (∼20% below individual energy requirements) and supervised endurance training resulting in ∼5% weight loss. Body composition was measured using dual energy X-ray absorptiometry. Insulin sensitivity was assessed during a hypersinsulinemic-euglycemic clamp. Cardiometabolic profile was derived from blood parameters. Subcutaneous fat and vastus lateralis muscle biopsies were used for ex vivo analyses. Two-way repeated-measure ANOVA and linear mixed models were used to evaluate the response to lifestyle intervention and comparison between the two groups. Fat mass was decreased and bone mass was preserved in the two groups after intervention. Muscle mass decreased significantly in older obese men. Cardiovascular risk (Framingham risk score, plasma triglyceride, and cholesterol) and insulin sensitivity were greatly improved to a similar extent in the two age groups after intervention. Changes in adipose tissue and skeletal muscle transcriptomes were marginal. Analysis of the differential response to the lifestyle intervention showed tenuous differences between age groups. These data suggest that lifestyle intervention combining calorie restriction and exercise shows similar beneficial effects on cardiometabolic risk and insulin sensitivity in younger and older obese men. However, attention must be paid to potential loss of muscle mass in response to weight loss in older obese men.NEW & NOTEWORTHY Rise in obesity and aging worldwide are major trends of critical importance in public health. This study addresses a current challenge in obesity management. Do older obese adults respond differently to a lifestyle intervention composed of moderate calorie restriction and supervised physical activity than younger ones? The main conclusion of the study is that older and younger obese men similarly benefit from the intervention in terms of cardiometabolic risk.

Published
2021
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28. MO441CALPROTECTIN IS A NOVEL CONTRIBUTING FACTOR IN VASCULAR CALCIFICATION AND A PREDICTOR OF CARDIOVASCULAR OUTCOME IN CKD PATIENTS*

Author

Joost P. Schanstra, Jose M. Valdivielso, Jean-Loup Bascands, Sam Hobson, Mylène Camus, Arnaud Del Bello, Odile Schiltz, Stanislas Faguer, Ana Amaya Garrido, Peter Stenvinkel, Alexis Piedrafita, Julie Klein, Bénédicte Buffin-Meyer, and Karolina Kublickiene

Subjects
Transplantation, medicine.medical_specialty, Iliac artery, business.industry, chemistry.chemical_element, Calcium, medicine.disease, Signal pathway, chemistry, Nephrology, Internal medicine, medicine, Cardiology, business, Vascular calcification, Calcification
Abstract

Background and Aims Vascular calcification, leading to aortic stiffening and heart failure, is decisive risk factor for cardiovascular (CV) mortality in patients with chronic kidney disease (CKD). Promoted by bone mineral disorder and systemic inflammation in CKD patients, vascular calcification is a complex mechanism involving osteochondrogenic differentiation of vascular smooth muscle cells (VSMCs) and abnormal deposition of minerals in the vascular wall. Despite intensive research efforts in recent years, available treatments have limited effect and none of them prevent or reverse vascular calcification. The aim of this study was to analyse the serum proteome of CKD stage 3-4 patients in order to unravel new molecular changes associated to CV morbid-mortality and to decipher the role of novel candidates on vascular calcification to provide potential new therapeutic agents. Method In this study we used serum samples from two independent cohorts: 112 CKD stage 3-4 patients with a 4 years follow-up for CV events and 222 CKD stage 5 patients exhibiting a broad range of calcification degree determined by histological quantification in the epigastric and/or iliac artery. Serum proteome analysis was performed using tandem mass-spectrometry in a subcohort of 66 CKD3-4 patients and validation of protein candidates was performed using ELISA in the two full cohorts. Human primary vascular smooth muscle cells and mouse aortic rings were used for calcification assays. Calcium content was quantified using QuantiChrom calcium assay kit and calcium deposition was visualized by Alizarin Red and Von Kossa staining. Results Among 443 proteins detected in the serum of CKD3-4 patients, 134 displayed significant modified abundance in patients with CV events (n=32) compared to patients without (n=34). One of the most prominent changes was increased level of calprotectin (up to 8.6 fold, P Conclusion Circulating calprotectin is a novel predictor of CV outcome and mortality in CKD patients. Calprotectin also shows calcification-inducing properties and its blockade by paquinimod alleviates its effects. Future experiments will consist in deciphering the signalling pathways involved in the regulation of calcification by calprotectin and evaluating in vivo the therapeutic potential of paquinimod on the development of medial vascular calcification lesions associated with CKD.

Published
2021
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29. Urinary Peptides as Potential Non-Invasive Biomarkers for Lupus Nephritis: Results of the Peptidu-LUP Study

Author

Maxence, Tailliar, Joost P, Schanstra, Tim, Dierckx, Benjamin, Breuil, Guillaume, Hanouna, Nicolas, Charles, Jean-Loup, Bascands, Bertrand, Dussol, Alain, Vazi, Laurent, Chiche, Justyna, Siwy, Stanislas, Faguer, Laurent, Daniel, Eric, Daugas, Noémie, Jourde-Chiche, On Behalf Of The Groupe Coopératif Sur le Lupus Rénal Gclr, Aix-Marseille Université - École de médecine (AMU SMPM MED), Aix-Marseille Université - Faculté des sciences médicales et paramédicales (AMU SMPM), Aix Marseille Université (AMU)-Aix Marseille Université (AMU), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Catholique de Louvain = Catholic University of Louvain (UCL), Des Maladies Rénales Rares aux Maladies Fréquentes, Remodelage et Réparation, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Bureau de Recherches Géologiques et Minières (BRGM) (BRGM), Diabète athérothrombose et thérapies Réunion Océan Indien (DéTROI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de La Réunion (UR), Aix Marseille Université (AMU), Hôpital Européen [Fondation Ambroise Paré - Marseille], Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM-TRANSFERT [Paris] (IT), Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
PREDICTION, ERYTHEMATOSUS, [SDV]Life Sciences [q-bio], non-invasive, kidney biopsy, lcsh:Medicine, PROGRESSION, DIAGNOSIS, CLASSIFICATION, VALIDATION, Article, Medicine, General & Internal, proteomics, systemic lupus erythematosus, General & Internal Medicine, lupus nephritis, Science & Technology, lcsh:R, CAPILLARY-ELECTROPHORESIS, peptidomics, KIDNEY-DISEASE, MASS-SPECTROMETRY, urine, RENAL-DISEASE, classification, biomarker, prognosis, Life Sciences & Biomedicine, prognosi
Abstract

Background: Lupus nephritis (LN) is a severe manifestation of Systemic Lupus Erythematosus (SLE). The therapeutic strategy relies on kidney biopsy (KB) results. We tested whether urinary peptidome analysis could non-invasively differentiate active from non-active LN. Design: Urinary samples were collected from 93 patients (55 with active LN and 38 with non-active LN), forming a discovery (n = 42) and an independent validation (n = 51) cohort. Clinical characteristics were collected at inclusion and prospectively for 24 months. The urinary peptidome was analyzed by capillary-electrophoresis coupled to mass-spectrometry, comparing active LN to non-active LN, and assessing chronic lesions and response to therapy. The value of previously validated prognostic (CKD273) and differential diagnostic (LN172) signatures was evaluated. Results: Urinary peptides could not discriminate between active and non-active LN or predict early response to therapy. Tubulo-interstitial fibrosis was correlated to the CKD273. The LN172 score identified 92.5% of samples as LN. Few patients developed new-onset CKD. Conclusions: We validated the CKD273 and LN172 classifiers but did not identify a robust signature that could predict active LN and replace KB. The value of urinary peptidome to predict long-term CKD, or renal flares in SLE, remains to be evaluated. ispartof: JOURNAL OF CLINICAL MEDICINE vol:10 issue:8 ispartof: location:Switzerland status: published

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2021
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30. Urinary peptides in heart failure: a link to molecular pathophysiology

Author

Shona M. Kerr, Javier Díez, Alex McConnachie, Faiez Zannad, William Mullen, Antonia Vlahou, Patrick Rossignol, Harald Mischak, Rafael Stroggilos, Vera Jankowski, Gerasimos Filippatos, Colette E. Jackson, Helle Bosselmann, Joost P. Schanstra, John J.V. McMurray, Jan A. Staessen, Agnieszka Latosinska, Zhenyu Zhang, Nicolas Girerd, Michaela Mischak, Christian Delles, Jane A. Cannon, Kasper Rossing, Archie Campbell, Andrew L. Clark, Alexandre Mebazaa, Ross T. Campbell, Morten Schou, Arantxa González, Tianlin He, Julia Raad, Mosaiques Diagnostics GmbH [Hanovre, Allemagne], Universitätsklinikum RWTH Aachen - University Hospital Aachen [Aachen, Germany] (UKA), Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), University of Hull [United Kingdom], Institute of Cardiovascular and Medical Sciences [Glasgow], University of Glasgow, Clínica Universidad de Navarra [Pamplona], Instituto de Investigación Sanitaria de Navarra [Pamplona, Spain] (IdiSNA), National and Kapodistrian University of Athens (NKUA), Attikon University Hospital, Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Service d'Anesthésie-Réanimation [AP-HP Hôpitaux Saint-Louis Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Biomedical Research Foundation of the Academy of Athens (BRFAA), Copenhagen University Hospital, University of Edinburgh, Western General Hospital, Edinburgh, Queen Elizabeth University Hospital (Glasgow), Harefield Hospital, Harefield, Herlev and Gentofte Hospital, Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), University Hospitals Leuven [Leuven], Non-Profit Research Institution Alliance for the Promotion of Preventive Medicine, AC, CD, JD, AG, AM, JR, NG, PR, FZ, HM, ZZ, JS, AL are supported by the EU Commission via the HOMAGE (HEALTH-FP7–305507 HOMAGE) project. CD, FZ, HM, JD and JS were previously supported by the EU-MASCARA (HEALTH-FP7–278249) project, and CD and JM receive support from the British Heart Foundation (RE/18/6/34217). TH is supported by the EU Commission via the CaReSyAn Project (MSCA-ITN-2017-Project ID: 764474). VJ is supported by the Deutsche Forschungsgemeinschaft' (DFG, German Research Foundation) by the Transregional Collaborative Research Centre (TRR 219, Project-ID 322900939) (subproject S-03). PR, NG, FZ are supported by the RHU Fight-HF, a public grant overseen by the French National Research Agency (ANR) as part of the second ‘Investissements d'Avenir’ program (reference: ANR-15-RHUS-0004), and by the French PIA project ‘Lorraine Université d'Excellence’(reference: ANR-15-IDEX-04-LUE). The Stanislas Cohort is sponsored by Nancy CHRU (France), its biobanking is managed by Biological Resource Center Lorrain BB-0033-00035. Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006] and is currently supported by the Wellcome Trust [216767/Z/19/Z]. The non-profit Research Institute Alliance for the Promotion of Preventive Medicine received a non-binding grant from OMRON Healthcare Co., Inc., Kyoto, Japan., ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), ANR-15-IDEX-0004,LUE,Isite LUE(2015), European Project: 305507,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,HOMAGE(2013), European Project: 278249,EC:FP7:HEALTH,FP7-HEALTH-2011-two-stage,EU-MASCARA(2011), European Project: 764474,CaReSyAn Project, RWTH Aachen University, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Université Sorbonne Paris Nord, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
collagen, medicine.medical_specialty, Proteome, Urinary system, proteome, Renal function, heart failure, 030204 cardiovascular system & hematology, Urine, Ventricular Function, Left, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Fibrosis, Diabetes mellitus, Internal medicine, medicine, Humans, Heart Failure, Ejection fraction, business.industry, fibrosis, Stroke Volume, Biomarker, medicine.disease, Prognosis, urine, 3. Good health, Blood pressure, Stroke Volume/physiology, Heart failure, Cardiology, Biomarker (medicine), biomarker, Collagen, Ventricular Function, Left/physiology, Cardiology and Cardiovascular Medicine, business, Peptides
Abstract

AIMS: Heart failure (HF) is a major public health concern worldwide. The diversity of HF makes it challenging to decipher the underlying complex pathological processes using single biomarkers. We examined the association between urinary peptides and HF with reduced (HFrEF), mid-range (HFmrEF) and preserved (HFpEF) ejection fraction, defined based on the European Society of Cardiology guidelines, and the links between these peptide biomarkers and molecular pathophysiology. METHODS AND RESULTS: Analysable data from 5608 participants were available in the Human Urinary Proteome database. The urinary peptide profiles from participants diagnosed with HFrEF, HFmrEF, HFpEF and controls matched for sex, age, estimated glomerular filtration rate, systolic and diastolic blood pressure, diabetes and hypertension were compared applying the Mann-Whitney test, followed by correction for multiple testing. Unsupervised learning algorithms were applied to investigate groups of similar urinary profiles. A total of 577 urinary peptides significantly associated with HF were sequenced, 447 of which (77%) were collagen fragments. In silico analysis suggested that urinary biomarker abnormalities in HF principally reflect changes in collagen turnover and immune response, both associated with fibrosis. Unsupervised clustering separated study participants into two clusters, with 83% of non-HF controls allocated to cluster 1, while 65% of patients with HF were allocated to cluster 2 (P

Published
2021
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31. The tryptophan pathway and nicotinamide supplementation in ischaemic acute kidney injury

Author

Alexis Piedrafita, Stéphane Balayssac, Julia Grossac, Nicolas Mayeur, Marie Buléon, Joost P. Schanstra, Melinda Alves, Stéphane Gazut, Stanislas Faguer, Bertrand Marcheix, Julie Klein, Vincent Minville, Institut National de la Santé et de la Recherche Médicale - INSERM, Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Pôle Anesthésie Réanimation [CHU de Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Laboratoire Sciences des Données et de la Décision (LS2D), Département Métrologie Instrumentation & Information (DM2I), Laboratoire d'Intégration des Systèmes et des Technologies (LIST (CEA)), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Laboratoire d'Intégration des Systèmes et des Technologies (LIST (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institut National de la Santé et de la Recherche Médicale (INSERM), Geroscience and rejuvenation research center (RESTORE), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Fondation pour la Recherche Médicale’ (grant DEQ20170336759), ANR-18-PERM-0003,KIDNEY ATTACK(2018), Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), CHU de Toulouse, Pole d'anesthésie Réanimation, Hôpital Paule de Viguier, Toulouse F-31059, France, CHU Toulouse [Toulouse], CEA, Université Paris-Saclay (CEA), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), arroyo, anne-marie, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, 030232 urology & nephrology, Pharmacology, urologic and male genital diseases, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, AKI, statistical analysis, [INFO.INFO-TS]Computer Science [cs]/Signal and Image Processing, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [CHIM] Chemical Sciences, Medicine, [CHIM]Chemical Sciences, AcademicSubjects/MED00340, signal processing, mass spectrometry, Transplantation, Nicotinamide, business.industry, Tryptophan, Acute kidney injury, biomarkers, medicine.disease, metabolomics, 3. Good health, 030104 developmental biology, chemistry, acute tubular necrosis, Nephrology, Original Article, ischaemia–reperfusion injury, business, cardiac surgery
Abstract

Background Down-regulation of the enzymes involved in tryptophan-derived nicotinamide (NAM) adenine dinucleotide (NAD+) production was identified after acute kidney injury (AKI), leading to the hypothesis that supplementation with NAM may increase the kidney NAD+ content, rescuing tryptophan pathways and subsequently improving kidney outcomes. Methods Urinary measurement of tryptophan and kynurenin using liquid chromatography–mass spectrometry metabolomics was used in a cohort of 167 cardiac bypass surgery patients along with tests for correlation to the development of postoperative AKI. A mouse model of ischaemic AKI using ischaemia–reperfusion injury (bilateral clamping of renal arteries for 25 min) was also used. Results We identified a significant decrease in urinary tryptophan and kynurenin in patients developing AKI, irrespective of the Kidney Disease: Improving Global Outcomes (KDIGO) stage. Although a significant difference was observed, tryptophan and kynurenin moderately discriminated for the development of all AKI KDIGO stages {area under the curve [AUC] 0.82 [95% confidence interval (CI) 0.75–0.88] and 0.75 [0.68–0.83], respectively} and severe KDIGO Stages 2–3 AKI [AUC 0.71 (95% CI 0.6–0.81) and 0.66 (0.55–0.77), respectively]. Sparked by this confirmation in humans, we aimed to confirm the potential preventive effect of NAM supplementation in wild-type male and female C57BL/6 mice subjected to ischaemic AKI. NAM supplementation had no effect on renal function (blood urea nitrogen at Day 1, sinistrin–fluorescein isothiocyanate glomerular filtration rate), architecture (periodic acid–Schiff staining) and injury or inflammation (kidney injury molecule 1 and IL18 messenger RNA expression). In addition, NAM supplementation did not increase post-AKI NAD+ kidney content. Conclusion Notwithstanding the potential role of NAM supplementation in the setting of basal NAD+ deficiency, our findings in mice and the reanalysis of published data do not confirm that NAM supplementation can actually improve renal outcomes after ischaemic AKI in unselected animals and probably patients.

Published
2021
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32. Administration of the High-Density Lipoprotein Mimetic CER-001 for Inherited Lecithin–Cholesterol Acyltransferase Deficiency

Author

Audrey Beq, Audrey Delas, Isabelle Labadens, Pauline Bernadet-Monrozies, Magali Colombat, Pascale Benlian, Dominique Chauveau, Vincent Soler, Stanislas Faguer, Joost P Schanstra, Antoine Huart, CHU Toulouse [Toulouse], Service de Néphrologie et Immunopathologie Clinique, Centre Hospitalier Universitaire de Toulouse, PRES Université de Toulouse, Service d'anatomie pathologique [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Pierre-Paul Riquet [Toulouse], and Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)

Subjects
medicine.medical_specialty, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), [SDV]Life Sciences [q-bio], Treatment outcome, Renal function, 030204 cardiovascular system & hematology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, High-density lipoprotein, Internal medicine, Internal Medicine, medicine, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Lecithin cholesterol acyltransferase deficiency, business.industry, Point mutation, General Medicine, medicine.disease, 3. Good health, Endocrinology, chemistry, business
Abstract

International audience

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2021
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33. Serum and urinary biomarkers of collagen type‐I turnover predict prognosis in patients with heart failure

Author

Joost P. Schanstra, Begoña López, Lutgarde Thijs, Yu-Ling Yu, Jan A. Staessen, Vera Jankowski, Andrew L. Clark, Javier Díez, Harald Mischak, Jesus D. Melgarejo, Zhenyu Zhang, Antonia Vlahou, Arantxa González, Tianlin He, Agnieszka Latosinska, John G.F. Cleland, Mosaiques Diagnostics GmbH [Hanovre, Allemagne], RWTH Aachen University, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University of Hull [United Kingdom], Clínica Universidad de Navarra [Pamplona], Institute of Health Carlos III, University Clinic of Navarra - CUN [Pamplona, Spain], University of Glasgow, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Biomedical Research Foundation of the Academy of Athens (BRFAA), Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), and Schanstra, Joost

Subjects
[SDV]Life Sciences [q-bio], Medicine (miscellaneous), Context (language use), Research & Experimental Medicine, 030204 cardiovascular system & hematology, Bioinformatics, Letter to Editor, Collagen Type I, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, EXTRACELLULAR-MATRIX, medicine, Humans, Risk factor, Pathological, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Heart Failure, Collagen type, 0303 health sciences, Science & Technology, business.industry, Organ dysfunction, Reproducibility of Results, Prognosis, medicine.disease, R1, Biobank, 3. Good health, [SDV] Life Sciences [q-bio], Oncology, Medicine, Research & Experimental, Heart failure, Cohort, Molecular Medicine, medicine.symptom, business, Life Sciences & Biomedicine, Biomarkers, Follow-Up Studies
Abstract

Clinical and translational medicine 11(1), e267 (2021). doi:10.1002/ctm2.267, Published by Wiley, Hoboken, NJ

Published
2021
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34. Mapping of the amniotic fluid proteome of fetuses with congenital anomalies of the kidney and urinary tract identifies plastin 3 as a protein involved in glomerular integrity

Author

Dominique Goudounèche, Brunhilde Wirth, Camille Fédou, Bénédicte Buffin-Meyer, Julie Batut, Quentin Bardou, Ophélie Lescat, Eric Neau, Mylène Camus, Sophie Dreux, Benjamin Breuil, Marie Buléon, Audrey Casemayou, Ivan Tack, Patrick Blader, Joost P. Schanstra, Guylène Feuillet, Stéphane Decramer, Franck Boizard, Bryony C Ross, Jean Sébastien Saulnier-Blache, Julie Klein, Melinda Alves, Ilka Mueller, Odile Burlet-Schiltz, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, University of Cologne, Centre de Microscopie Électronique Appliquée à la Biologie (CMEAB), Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Toulouse Réseau Imagerie-Genotoul ( TRI-Genotoul), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital Robert Debré, Unité de biologie moléculaire, cellulaire et du développement (MCD), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), CHU Toulouse [Toulouse], Centre de référence des maladies rénales rares (SORARE), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Institute of Occupational Medicine [Edinburgh] (IOM), Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse Réseau Imagerie-Genotoul ( TRI-Genotoul), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Saulnier-Blache, Jean Sébastien, Unité de biologie moléculaire, cellulaire et du développement - UMR5077 (MCD), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)

Subjects
0301 basic medicine, Male, Pathology, medicine.medical_specialty, podocyte, Proteome, [SDV]Life Sciences [q-bio], Podocyte foot, nephrogenesis, Fetal Kidney, Pathology and Forensic Medicine, Podocyte, Nephrin, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, proteomics, medicine, Animals, Humans, Zebrafish, ComputingMilieux_MISCELLANEOUS, CAKUT, Vesico-Ureteral Reflux, Kidney, Membrane Glycoproteins, biology, plastin 3, Microfilament Proteins, amniotic fluid, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], fetus, 030104 developmental biology, medicine.anatomical_structure, Podocalyxin, chemistry, 030220 oncology & carcinogenesis, Urogenital Abnormalities, biology.protein, Albuminuria, Female, medicine.symptom, chronic kidney disease, Kidney disease
Abstract

International audience; Congenital anomalies of the kidney and the urinary tract (CAKUT) are the first cause of chronic kidney disease in childhood. Several genetic and environmental origins are associated with CAKUT, but most pathogenic pathways remain elusive. Considering the amniotic fluid (AF) composition as a proxy for fetal kidney development, we analyzed the AF proteome from non-severe CAKUT (n = 19), severe CAKUT (n = 14), and healthy control (n = 22) fetuses using LC-MS/MS. We identified 471 significant proteins that discriminated the three AF groups with 81% precision. Among them, eight proteins independent of gestational age (CSPG4, LMAN2, ENDOD1, ANGPTL2, PRSS8, NGFR, ROBO4, PLS3) were associated with both the presence and the severity of CAKUT. Among those, five were part of a protein-protein interaction network involving proteins previously identified as being potentially associated with CAKUT. The actin-bundling protein PLS3 (plastin 3) was the only protein displaying a gradually increased AF abundance from control, via non-severe, to severe CAKUT. Immunohistochemistry experiments showed that PLS3 was expressed in the human fetal as well as in both the fetal and the postnatal mouse kidney. In zebrafish embryos, depletion of PLS3 led to a general disruption of embryonic growth including reduced pronephros development. In postnatal Pls3-knockout mice, kidneys were macroscopically normal, but the glomerular ultrastructure showed thickening of the basement membrane and fusion of podocyte foot processes. These structural changes were associated with albuminuria and decreased expression of podocyte markers including Wilms' tumor-1 protein, nephrin, and podocalyxin. In conclusion, we provide the first map of the CAKUT AF proteome that will serve as a reference for future studies. Among the proteins strongly associated with CAKUT, PLS3 did surprisingly not specifically affect nephrogenesis but was found as a new contributor in the maintenance of normal kidney function, at least in part through the control of glomerular integrity. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Published
2021
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35. Connectivity mapping of glomerular proteins identifies dimethylaminoparthenolide as a new inhibitor of diabetic kidney disease

Author

Julie Klein, Cécile Caubet, Mylène Camus, Manousos Makridakis, Colette Denis, Marion Gilet, Guylène Feuillet, Simon Rascalou, Eric Neau, Luc Garrigues, Olivier Thillaye du Boullay, Harald Mischak, Bernard Monsarrat, Odile Burlet-Schiltz, Antonia Vlahou, Jean Sébastien Saulnier-Blache, Jean-Loup Bascands, Joost P. Schanstra, Equipe 7 Inserm U1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Evotec (France) SAS [Toulouse], Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Biomedical Research Foundation of the Academy of Athens (BRFAA), Laboratoire Hétérochimie Fondamentale et Appliquée (LHFA), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD), Mosaiques Diagnostics GmbH [Hanovre, Allemagne], Diabète athérothrombose et thérapies Réunion Océan Indien (DéTROI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de La Réunion (UR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Evotec [Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Saulnier-Blache, Jean Sébastien, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Proteomics, Male, [SDV]Life Sciences [q-bio], Kidney Glomerulus, lcsh:Medicine, Angiotensin-Converting Enzyme Inhibitors, Diabetic nephropathy, Article, Renin-Angiotensin System, Angiotensin Receptor Antagonists, Mice, Chronic kidney disease, Connectome, Animals, Diabetic Nephropathies, lcsh:Science, Kidney diseases, Drug discovery, lcsh:R, Diagnostic markers, Computational biology and bioinformatics, [SDV] Life Sciences [q-bio], Mice, Inbred C57BL, Diabetes Mellitus, Type 1, Gene Expression Regulation, Nephrology, lcsh:Q, Sesquiterpenes, Biomarkers, Glomerular Filtration Rate
Abstract

International audience; Abstract While blocking the renin angiotensin aldosterone system (RAAS) has been the main therapeutic strategy to control diabetic kidney disease (DKD) for many years, 25–30% of diabetic patients still develop the disease. In the present work we adopted a systems biology strategy to analyze glomerular protein signatures to identify drugs with potential therapeutic properties in DKD acting through a RAAS-independent mechanism. Glomeruli were isolated from wild type and type 1 diabetic (Ins2Akita) mice treated or not with the angiotensin-converting enzyme inhibitor (ACEi) ramipril. Ramipril efficiently reduced the urinary albumin/creatine ratio (ACR) of Ins2Akita mice without modifying DKD-associated renal-injuries. Large scale quantitative proteomics was used to identify the DKD-associated glomerular proteins (DKD-GPs) that were ramipril-insensitive (RI-DKD-GPs). The raw data are publicly available via ProteomeXchange with identifier PXD018728. We then applied an in silico drug repurposing approach using a pattern-matching algorithm (Connectivity Mapping) to compare the RI-DKD-GPs’s signature with a collection of thousands of transcriptional signatures of bioactive compounds. The sesquiterpene lactone parthenolide was identified as one of the top compounds predicted to reverse the RI-DKD-GPs’s signature. Oral treatment of 2 months old Ins2Akita mice with dimethylaminoparthenolide (DMAPT, a water-soluble analogue of parthenolide) for two months at 10 mg/kg/d by gavage significantly reduced urinary ACR. However, in contrast to ramipril, DMAPT also significantly reduced glomerulosclerosis and tubulointerstitial fibrosis. Using a system biology approach, we identified DMAPT, as a compound with a potential add-on value to standard-of-care ACEi-treatment in DKD.

Published
2020
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36. The low affinity p75 neurotrophin receptor is down-regulated in congenital anomalies of the kidney and the urinary tract: Possible involvement in early nephrogenesis

Author

Ophélie Lescat, Camille Fédou, Patrick Blader, Jean Sébastien Saulnier-Blache, Julie Klein, Joost P. Schanstra, Guylène Feuillet, Marie Buléon, Bénédicte Buffin-Meyer, Eric Neau, Stéphane Decramer, Julie Batut, Melinda Alves, Benjamin Breuil, Laboratoire de Physique Statistique de l'ENS (LPS), Université Paris Diderot - Paris 7 (UPD7)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Morpholino, Urinary system, [SDV]Life Sciences [q-bio], Biophysics, Down-Regulation, Nerve Tissue Proteins, Receptors, Nerve Growth Factor, Kidney, Biochemistry, Fetal Kidney, Pronephros, 03 medical and health sciences, Mice, 0302 clinical medicine, medicine, Animals, Humans, RNA, Messenger, Urinary Tract, Molecular Biology, Zebrafish, ComputingMilieux_MISCELLANEOUS, Fetus, biology, urogenital system, Cell Biology, biology.organism_classification, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Mesangium, 030220 oncology & carcinogenesis, embryonic structures, sense organs
Abstract

Congenital Anomalies of the Kidney and of the Urinary Tract (CAKUT) cover a broad range of disorders including abnormal kidney development caused by defective nephrogenesis. Here we explored the possible involvement of the low affinity p75 neurotrophin receptor (p75NTR) in CAKUT and nephrogenesis. In mouse, p75NTR was highly expressed in fetal kidney, located within cortical early nephrogenic bodies, and decreased rapidly after birth. In human control fetal kidney, p75NTR was also located within the early nephrogenic bodies as well as in the mature glomeruli, presumably in the mesangium. In CAKUT fetal kidneys, the kidney cortical structure and the localization of p75NTR were often disorganized, and quantification of p75NTR in amniotic fluid revealed a significant reduction in CAKUT compared to control. Finally, invalidation of p75NTR in zebrafish embryo with an antisense morpholino significantly altered pronephros development. Our results indicate that renal p75NTR is altered in CAKUT fetuses, and could participate to early nephrogenesis.

Published
2020
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37. Molecular Changes in Tissue Proteome during Prostate Cancer Development: Proof-of-Principle Investigation

Author

William Mullen, Manousos Makridakis, Harald Mischak, Katarina Davalieva, Maria Frantzi, Joost P. Schanstra, Antonia Vlahou, Agnieszka Latosinska, Mosaiques Diagnostics & Therapeutics (MOSAIQUES DIAGNOSTICS & THERAPEUTICS), Mosaiques Diagnostics & Therapeutics AG, Macedonian Academy of Sciences and Arts [Skopje, North Macedonia] (MASA), Biomedical Research Foundation of the Academy of Athens (BRFAA), Institute of Cardiovascular and Medical Sciences [Glasgow], University of Glasgow, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), and Schanstra, Joost

Subjects
0301 basic medicine, In silico, [SDV]Life Sciences [q-bio], Clinical Biochemistry, drug target, Computational biology, Biology, Tandem mass spectrometry, Proteomics, urologic and male genital diseases, Interactome, Article, Transcriptome, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, proteomics, medicine, tissue, lcsh:R5-920, Endoplasmic reticulum, personalized medicine, medicine.disease, prostate cancer, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, 030220 oncology & carcinogenesis, Proteome, lcsh:Medicine (General)
Abstract

International audience; (1) Background: Prostate cancer (PCa) is characterized by high heterogeneity. The aim of this study was to investigate molecular alterations underlying PCa development based on proteomics data. (2) Methods: Liquid chromatography coupled to tandem mass spectrometry was conducted for 22 fresh-frozen tissue specimens from patients with benign prostatic hyperplasia (BPH, n = 5) and PCa (n = 17). Mann Whitney test was used to define significant differences between the two groups. Association of protein abundance with PCa progression was evaluated using Spearman correlation, followed by verification through investigating the Prostate Cancer Transcriptome Atlas. Functional enrichment and interactome analysis were carried out using Metascape and String. (3) Results: Proteomics analysis identified 1433 proteins, including 145 proteins as differentially abundant between patients with PCa and BPH. In silico analysis revealed alterations in several pathways and hallmarks implicated in metabolism and signalling, represented by 67 proteins. Among the latter, 21 proteins were correlated with PCa progression at both the protein and mRNA levels. Interactome analysis of these 21 proteins predicted interactions between Myc proto-oncogene (MYC) targets, protein processing in the endoplasmic reticulum, and oxidative phosphorylation, with MYC targets having a central role. (4) Conclusions: Tissue proteomics allowed for characterization of proteins and pathways consistently affected during PCa development. Further validation of these findings is required.

Published
2020
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38. Amniotic fluid peptides predict postnatal kidney survival in developmental kidney disease

Author

Romain Favre, Marie-Pierre Lavocat, Bernard Boudailliez, Charlotte Lucas, Camille Fédou, Jean-Sebastien Saulnier Blache, Anne-Sophie Weingertner, Blandine Hougas, Joost P. Schanstra, Pascal Gaucherand, Sylvie Cloarec, Julie Batut, Catherine Noel, J. Gondry, Philippe Eckart, Norbert Winer, Benjamin Breuil, Gérard Champion, Jean-Baptiste Benevent, Franck Perrotin, Christophe Vayssière, Florence Biquard, Harald Mischak, Gwenaelle Le Bouar, Jérôme Massardier, Françoise Conte Auriol, Pedro Magalhães, Sophie Martin, Jean-Paul Bory, Sophie Collardeau-Frachon, Eve Mousty, Lucie Bessenay, Corinne Floch, Julie Klein, Amelie Ryckewaert, Elisabeth Simon, Alain Martin, Guylène Bourdat-Michel, Marie-Françoise Froute, Franz Schaefer, Pascale Marcorelles, Stéphane Decramer, Nabila Moussaoui, Franck Boizard, Marie-Christine Manca-Pellissier, Mariannick Maupin-Hyvonnet, Marion Groussolles, Jean-Marie Delbosc, Guylène Feuillet, Anke Raaijmakers, François Nobili, Sophie Taque, Petra Zürbig, Vincent Guigonis, Audrey Casemayou, Patrick Blader, An Hindryckx, Luc Decatte, Karel Allegaert, Ophélie Lescat, Eric Neau, Odile Basmaison, Emma Allain-Launay, Agnes Sartor, Jean-Loup Bascands, Claudine Le Vaillant, Hélène Laurichesse Delmas, Bénédicte Buffin-Meyer, Nadia Lounis, Anne-Hélène Saliou, Véronique Baudouin, Elena Levtchenko, Maryse Fiorenza, Christine Pietrement, Valérie Goua, Marina Merveille, Laurent Bidat, Yves Aubard, Alexandra Benachi, Sylvie Kessler, Loic De Parscau, Jean-François Oury, Fabienne Prieur, Centre de biologie du développement (CBD), Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Equipe 7 Inserm U1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Fédérale Toulouse Midi-Pyrénées, University Hospitals Leuven [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Laboratoire de Gérontechnologie [Hôpital La Grave-CHU de Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Gérontopôle, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Gatien de Clocheville [Tours] (CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Clermont-Ferrand, Centre hospitalier universitaire de Nantes (CHU Nantes), Groupe de Recherche sur l'Analyse Multimodale de la Fonction Cérébrale - UMR INSERM_S 1105 (GRAMFC), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Amiens-Picardie, Centre Hospitalier Universitaire de Nice (CHU Nice), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Hôpital Morvan - CHRU de Brest (CHU - BREST ), Centre Hospitalier René Dubos [Pontoise], Hôpital Louis Mourier - AP-HP [Colombes], Centre Hospitalier Universitaire [Grenoble] (CHU), Les Hôpitaux Universitaires de Strasbourg (HUS), AP-HP Hôpital universitaire Robert-Debré [Paris], Centre Hospitalier Universitaire de Reims (CHU Reims), Hospices Civils de Lyon (HCL), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Centre de dépistage des Carmes [Toulouse] (CDC), Hôpital des Enfants, CHU Toulouse [Toulouse], Laboratoire sur les interactions Epithéliums Neurones (LIEN), Université de Brest (UBO), Département de Pathologie [CHU Lyon-Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Mosaiques Diagnostics & Therapeutics AG [Hannover, Germany], University of Glasgow, Hannover Medical School [Hannover] (MHH), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre de Biologie Intégrative (CBI), Diabète athérothrombose et thérapies Réunion Océan Indien (DéTROI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de La Réunion (UR), Heidelberg University, Centre De Référence des Maladies Rénales Rares du Sud Ouest (SORARE), Centre De Référence des Maladies Rénales Rares du Sud Ouest, BIOMAN consortium: Karel Allegaert, Yves Aubard, Odile Basmaison, Jean-Baptiste Benevent, Florence Biquard, Gérard Champion, Jean-Marie Delbosc, Philippe Eckart, Marie-Françoise Froute, Pascal Gaucherand, Marion Groussolles, Vincent Guigonis, Blandine Hougas, Gwenaelle Le Bouar, Alain Martin, Sophie Martin, Mariannick Maupin-Hyvonnet, Marina Merveille, Eve Mousty, François Nobili, Amelie Ryckewaert, Agnes Sartor, Sophie Taque, Norbert Winer, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Development and Regeneration, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Gérontopôle-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse], Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Clocheville, Department of Pediatric and Prenatal Radiology, Timone's Children-Hospital (APHM), Hôpital Dupuytren [CHU Limoges], CHU Toulouse, Hôpital des Enfants, Unité de Gastroentérologie, Hépatologie et Nutrition, Département de Pédiatrie, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Groupement Hospitalier Est [Bron], University Medical Center Heidelberg, Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Saulnier-Blache, Jean Sébastien, Pôle Gériatrie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), and Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Amniotic fluid, Urinary system, [SDV]Life Sciences [q-bio], congenital anomalies of the kidney and the urinary tract, 030232 urology & nephrology, Kidney, Fetal Kidney, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, medicine, Animals, Humans, termination of pregnancy, Prospective Studies, Child, Urinary Tract, Zebrafish, ComputingMilieux_MISCELLANEOUS, Fetus, business.industry, infants, Area under the curve, amniotic fluid, prediction, medicine.disease, 3. Good health, Pronephros, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, Nephrology, Urogenital Abnormalities, peptides, Female, Kidney Diseases, business, management, Kidney disease
Abstract

Although a rare disease, bilateral congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of end stage kidney disease in children. Ultrasound-based prenatal prediction of postnatal kidney survival in CAKUT pregnancies is far from accurate. To improve prediction, we conducted a prospective multicenter peptidome analysis of amniotic fluid spanning 140 evaluable fetuses with CAKUT. We identified a signature of 98 endogenous amniotic fluid peptides, mainly composed of fragments from extracellular matrix proteins and from the actin binding protein thymosin-β4. The peptide signature predicted postnatal kidney outcome with an area under the curve of 0.96 in the holdout validation set of patients with CAKUT with definite endpoint data. Additionally, this peptide signature was validated in a geographically independent sub-cohort of 12 patients (area under the curve 1.00) and displayed high specificity in non-CAKUT pregnancies (82 and 94% in 22 healthy fetuses and in 47 fetuses with congenital cytomegalovirus infection respectively). Change in amniotic fluid thymosin-β4 abundance was confirmed with ELISA. Knockout of thymosin-β4 in zebrafish altered proximal and distal tubule pronephros growth suggesting a possible role of thymosin β4 in fetal kidney development. Thus, recognition of the 98-peptide signature in amniotic fluid during diagnostic workup of prenatally detected fetuses with CAKUT can provide a long-sought evidence base for accurate management of the CAKUT disorder that is currently unavailable. ispartof: KIDNEY INTERNATIONAL vol:99 issue:3 pages:737-749 ispartof: location:United States status: published

Published
2020
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39. P0652THYMOSIN BETA 4 AND KIDNEY FUNCTION: AN INVERSE RELATIONSHIP?

Author

Justyna Siwy, Joachim Beige, Joost P. Schanstra, Tianlin He, Harald Mischak, and Agnieszka Latosinska

Subjects
Transplantation, Kidney, medicine.medical_specialty, business.industry, Inverse, Renal function, medicine.disease, medicine.anatomical_structure, Endocrinology, Animal model, Nephrology, Fibrosis, Internal medicine, medicine, Albuminuria, Cellular Morphology, medicine.symptom, Beta (finance), business
Abstract

Background and Aims Thymosin β4 (Tβ4) is an abundant peptide in urine and plasma, involved in multiple processes including cell morphology, wound healing, and inflammation. A major, yet not well defined role of Tβ4 was described in the context of kidney and cardiovascular disease. Knock out of Tβ4 resulted, among others, in increased albuminuria in a nephrotoxic nephritis model. In animal models it has been shown that Tβ4 can modify renal and cardiovascular disease, fibrosis and inflammation. However, most of the data are derived from animal models and the relevance of Tβ4 in human is less clear. As a first step towards investigating the potential relevance of Tβ4 in chronic kidney disease (CKD) in human, we investigated the abundance of Tβ4 in human urine. Method We investigated human urine in 2240 subjects with a wide spread of kidney function for the presence of Tβ4 using capillary-electrophoresis coupled mass spectrometry (CE-MS) and tandem mass spectrometry. In addition, we evaluated the presence of Tβ4 abundance in hemodialysis fluid of 10 subjects. Results The full length acetylated Tβ4 peptide could be identified in human urine in high abundance (molecular mass 4960.485 Da). In addition, an oxidized isoform could also be observed at high abundance. When investigating the distribution of both isoforms in control subjects and patients at different stages of CKD, a highly significant inverse association of the abundance of Tβ4 with eGFR could be observed for both, with rho -0.388 for the non-oxidized and -0.387 for the oxidized isoform, p Conclusion Tβ4 is highly significantly inversely associated with kidney function, suggesting a role of Tβ4 in kidney disease and/or its complications. Based on the experimental data published from animal models, the increase in Tβ4 may reflect a potential physiological mechanism to counteract CKD and its complications. Investigation of association of Tβ4 levels with progression in CKD, cardiovascular complications and death may inform on a potentially beneficial effect of Tβ4, is currently ongoing in longitudinal datasets and will be presented.

Published
2020
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40. P0724ASSOCIATIONS OF URINARY POLYMERIC IMMUNOGLOBULIN RECEPTOR PEPTIDES IN THE CONTEXT OF CARDIO-RENAL SYNDROM

Author

William Mullen, Jochen Metzger, Petra Zürbig, Justyna Siwy, Joost P. Schanstra, Tianlin He, Vera Jankowski, and Harald Mischak

Subjects
Transplantation, medicine.medical_specialty, Kidney, biology, Secretory component, business.industry, Urinary system, Coronary arteriosclerosis, Context (language use), Endocrinology, medicine.anatomical_structure, Nephrology, Peptide Hydrolases, Internal medicine, medicine, biology.protein, Antibody, Polymeric immunoglobulin receptor, business
Abstract

Background and Aims The polymeric immunoglobulin receptor (pIgR) which transports immunoglobulins from the basolateral to the apical surface of epithelial cells was recently shown to be associated with kidney dysfunction. The immune defense is initiated at the apical surface where the N-terminal domain of pIgR, termed secretory component (SC), is proteolytically cleaved and released either unbound (free SC) or bound to immunoglobulins. The aim of our study was to show the association of pIgR peptides with the cardio-renal syndrome in a large cohort and to get information on how the SC will be released. Method We investigated urinary peptides of 2707 individuals available in the Human Urine Proteome Database using capillary electrophoresis coupled to mass spectrometry. Results The mean abundance of 23 different pIgR peptides correlates negatively with the estimated glomerular filtration rate (eGFR, r=-0.314, p Conclusion In this large cohort, we could demonstrate that pIgR is associated with the cardio-renal syndrome and provide more detailed insights on how pIgR can be potentially cleaved to release the SC.

Published
2020
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41. P0360URINARY PEPTIDOMIC ANALYSIS IN PROLIFERATIVE VERSUS NON-PROLIFERATIVE LUPUS NEPHRITIS : RESULTS OF THE PEPTIDU-LUP STUDY

Author

Justyna Siwy, Tim Dierckx, Bertrand Dussol, Stanislas Faguer, Laurent Daniel, Guillaume Hanouna, Breuil Benjamin, Stéphane Burtey, Joost P. Schanstra, Laurent Chiche, Mickaël Bobot, Maxence Tailliar, Noémie Jourde-Chiche, and Eric Daugas

Subjects
Transplantation, medicine.diagnostic_test, biology, business.industry, Anti-dsDNA antibodies, Lupus nephritis, Glomerulosclerosis, Glomerulonephritis, Interstitial fibrosis, medicine.disease, Nephrology, Immunology, biology.protein, Medicine, Renal biopsy, business
Abstract

Background and Aims Lupus nephritis (LN) is a frequent manifestation of Systemic Lupus Erythematosus (SLE). The therapeutic strategy relies on the result of kidney biopsy, which differentiates proliferative LN (PLN) from non-proliferative LN (NPLN). The analysis of the urinary peptidome has led to the identification of prognostic biomarkers in chronic kidney disease (CKD, namely the CKD273 classifier), or, as a liquid biopsy, for the diagnosis of glomerulonephritides. We verified whether urinary peptidomics could predict the severity of renal pathological injury and damage in LN. Method Urine samples, collected before kidney biopsy, were analyzed by capillary-electrophoresis coupled to mass-spectrometry (CE-MS). Urinary peptide profiles were compared between PLN and NPLN. Predictive values for chronic pathological lesions (glomerulosclerosis and interstitial fibrosis/tubular atrophy (IF/TA)), response to therapy and development of CKD were also assessed. Clinical characteristics, routine laboratory parameters and immunological SLE markers were collected at inclusion and prospectively for at least 24 months. Results We collected 100 urinary samples from patients with LN, forming a discovery (n=67) and an independent validation (n=33) cohort. Overall there were 69 patients with PLN (class III or IV +/-V with active lesions) and 31 patients with NPLN (class II or V or chronic lesions). In the discovery cohort, the abundance of 36 urinary peptides differed between PLN and NPLN (Mann-Whitney test). However, these peptides did not resist multiple testing correction. Among them, 17 could be sequenced (fragments of collagen-I, -II, -III, apolipoprotein A-I, Fibrinogen alpha chain and Histone H2B). Of the 17 sequenced peptides, 7 were also part of the CKD273 classifier. A mathematical model combining the 36 peptides classified PLN and NPLN patients from the validation cohort with an AUC of 0.75 and sensitivity and specificity of 0.81 and 0.53, respectively. Positivity of anti-dsDNA antibodies had the best sensitivity (0.96) and sterile pyuria the best specificity (0.68) to differentiate PLN from NPLN, and including the CKD273 score did not improve the accuracy of the predictive models. No urinary peptidomics profile was identified to predict early response to therapy in patients with LN. Glomerulosclerosis was observed in 63/100 biopsies. In the discovery cohort, the abundance of 38 urinary peptides (including 22 sequenced) differed between patients with vs without glomerulosclerosis (Mann-Whitney test). Again, these peptides did not resist multiple testing correction. Of the 22 sequenced peptides, 7 (different from the peptides associated with PLN) belonged to the CKD273 classifier. A mathematical model combining the 38 peptides classified patients from the validation cohort with an AUC of 0.75 and sensitivity and specificity of 0.82 and 0.54, respectively, for the presence of glomerulosclerosis. Although the quantification of IF/TA was correlated to the pre-existing CKD273 classifier, including the CKD273 score did not improve the prediction of IF/TA when tested in combination with simple clinical parameters. Only 3 patients developed CKD after a mean follow-up of 4 years, therefore contribution of urinary peptidomics for the prediction of CKD in LN could not be evaluated. Conclusion Different urinary peptidomics signatures were identified among patients with LN, according to the presence of active proliferative lesions or chronic lesions. However, these panels did not resist multiple testing correction, and did not improve the diagnostic accuracy when combined with clinical or immunological markers. The contribution of urinary peptidomics to predict CKD in patients with LN, or as an early predictor of renal flares, could not be evaluated. Kidney biopsy remains central for the care of patients with LN.

Published
2020
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42. Urinary peptidomics in kidney disease and drug research

Author

Magdalena Krochmal, Joost P. Schanstra, and Harald Mischak

Subjects
Proteomics, 0301 basic medicine, Drug, Biomedical Research, media_common.quotation_subject, Urinary system, Context (language use), Bioinformatics, Translational Research, Biomedical, 03 medical and health sciences, Drug Discovery, medicine, Animals, Humans, In patient, media_common, Kidney, business.industry, medicine.disease, Biomarker (cell), 030104 developmental biology, medicine.anatomical_structure, Kidney Diseases, Peptides, business, Kidney disease
Abstract

Due to its close connection with the renal system, urine is considered a valuable source of information in kidney disease research. Peptidomics methods focus on the discovery of endogenous peptides, given their wide range of biological functions and diagnostic and therapeutic potential. Representing a non-invasive and sensitive method, technological prospects of urinary peptidomics should be evaluated in the context of drug discovery and research. Areas covered: This review describes urinary peptidomics with focus on its application in drug research in the field of kidney diseases. The authors provide an overview of current achievements and potential future applications. Expert opinion: The urinary peptidome is a dynamically changing source of information, able to reflect sudden and long-term changes affecting the renal system. Studies utilizing urinary peptidomics techniques have demonstrated their value in patient stratification and detection of early pathological changes in kidney disease. Serving as a liquid biopsy, urinary peptides are an invaluable tool for drug response monitoring. Nevertheless, peptidomics is largely underexplored in drug research in general, as evidenced by the scarce number of scientific publications on this topic. Further progress will be driven by the successful validation of current discoveries and continued efforts to improve the translation of results into therapeutic applications.

Published
2017
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43. A urinary proteome-based classifier for the early detection of decline in glomerular filtration

Author

Harald Mischak, Justyna Siwy, Peter Rossing, Joost P. Schanstra, Lotte Jacobs, Raymond Vanholder, Claudia Pontillo, Joachim Jankowski, Jan A. Staessen, Petra Zürbig, Antonia Vlahou, Hiddo J. Lambers Heerspink, William Mullen, Pathologie, RS: CARIM - R3.06 - The vulnerable plaque: makers and markers, Groningen Kidney Center (GKC), Methods in Medicines evaluation & Outcomes research (M2O), and Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET)

Subjects
0301 basic medicine, Male, CHRONIC KIDNEY-DISEASE, Proteome, PROGRESSION, Urine, Diabetic nephropathy, Cohort Studies, FIBROSIS, POPULATION, education.field_of_study, Kidney, PEPTIDES, Middle Aged, proteome analysis, BIOMARKER DISCOVERY, urine, 3. Good health, medicine.anatomical_structure, Nephrology, Disease Progression, Female, medicine.symptom, Glomerular Filtration Rate, medicine.medical_specialty, Urinary system, Population, Urology, Renal function, DIAGNOSIS, albuminuria, VALIDATION, DIABETIC-NEPHROPATHY, 03 medical and health sciences, Internal medicine, medicine, CKD273, Humans, Renal Insufficiency, Chronic, education, Transplantation, business.industry, MASS-SPECTROMETRY, medicine.disease, 030104 developmental biology, Endocrinology, Early Diagnosis, Albuminuria, business, Biomarkers, chronic kidney disease, Kidney disease
Abstract

BACKGROUND: Chronic kidney disease (CKD) progression is currently assessed by a decline in estimated glomerular filtration rate (eGFR) and/or an increase in urinary albumin excretion (UAE). However, these markers are considered either to be late-stage markers or to have low sensitivity or specificity. In this study, we investigated the performance of the urinary proteome-based classifier CKD273, compared with UAE, in a number of different narrow ranges of CKD severity, with each range separated by an eGFR of 10 mL/min/1.73 m 2 . METHODS: A total of 2672 patients with different CKD stages were included in the study. Of these, 394 individuals displayed a decline in eGFR of >5 mL/min/1.73 m 2 /year (progressors) and the remaining individuals were considered non-progressors. For all samples, UAE values and CKD273 classification scores were obtained. To assess UAE values and CKD273 scores at different disease stages, the cohort was divided according to baseline eGFRs of ≥80, 70-79, 60-69, 50-59, 40-49, 30-39 and

Published
2017
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44. Hepatocyte Nuclear Factor-1β Controls Mitochondrial Respiration in Renal Tubular Cells

Author

Audren Fournel, Jean-Loup Bascands, Dimitri Marsal, Marion Gillet, Stanislas Faguer, Nicolas Chassaing, Audrey Casemayou, Stéphane Decramer, Claude Knauf, Julie Belliere, Marco Pontoglio, Joost P. Schanstra, Alessia Bagattin, Antoine Huart, and Dominique Chauveau

Subjects
0301 basic medicine, medicine.medical_specialty, Inflammation, General Medicine, Mitochondrion, Biology, Cell biology, Proinflammatory cytokine, 03 medical and health sciences, Hepatocyte nuclear factors, 030104 developmental biology, Endocrinology, Mitochondrial biogenesis, Downregulation and upregulation, Nephrology, Internal medicine, Coactivator, medicine, PPARGC1A, medicine.symptom
Abstract

AKI is a frequent condition that involves renal microcirculation impairment, infiltration of inflammatory cells with local production of proinflammatory cytokines, and subsequent epithelial disorders and mitochondrial dysfunction. Peroxisome proliferator-activated receptor γ coactivator 1-α (PPARGC1A), a coactivator of the transcription factor PPAR-γ that controls mitochondrial biogenesis and function, has a pivotal role in the early dysfunction of the proximal tubule and the subsequent renal repair. Here, we evaluated the potential role of hepatocyte nuclear factor-1β (HNF-1β) in regulating PPARGC1A expression in AKI. In mice, endotoxin injection to induce AKI also induced early and transient inflammation and PPARGC1A inhibition, which overlapped with downregulation of the HNF-1β transcriptional network. In vitro, exposure of proximal tubule cells to the inflammatory cytokines IFN-γ and TNF-α led to inhibition of HNF-1β transcriptional activity. Moreover, inhibition of HNF-1β significantly reduced PPARGC1A expression and altered mitochondrial morphology and respiration in proximal tubule cells. Chromatin immunoprecipitation assays and PCR analysis confirmed HNF-1β binding to the Ppargc1a promoter in mouse kidneys. We also demonstrated downregulation of renal PPARGC1A expression in a patient with an HNF1B germinal mutation. Thus, we propose that HNF-1β links extracellular inflammatory signals to mitochondrial dysfunction during AKI partly via PPARGC1A signaling. Our findings further strengthen the view of HNF1B-related nephropathy as a mitochondrial disorder in adulthood.

Published
2017
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45. Urinary lysophopholipids are increased in diabetic patients with nephropathy

Author

Jean-Michel Halimi, Pierre Gourdy, Ronan Roussel, Joost P. Schanstra, Samy Hadjadj, Jean-Loup Bascands, Aude Dupuy, Eva Feigerlova, Jean-Sébastien Saulnier-Blache, Bruno Guerci, Justine Bertrand-Michel, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées, CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pôle DUNE, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Université de Poitiers - Faculté de Médecine et de Pharmacie, Université de Poitiers, Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de néphrologie et immunologie clinique, Hôpital Bretonneau-Université de Tours-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Cellules Dendritiques, Immunomodulation et Greffes [Tours] (UFR de Médecine - EA4245), Université Francois Rabelais [Tours], Service de Diabétologie, Maladies Métaboliques et Nutrition, CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Déterminants génétiques du diabète de type 2 et de ses complications vasculaires ((U 695)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7), Métabolisme et physiologie rénale (CRC - UMR_S 1138), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), DHU FIRE Centre de compétence des maladies pulmonaires rares, Diabète athérothrombose et thérapies Réunion Océan Indien (DéTROI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de La Réunion (UR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours, École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de néphrologie et immunologie clinique [CHRU Tours], and Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours (UT)

Subjects
Male, 0301 basic medicine, [SDV]Life Sciences [q-bio], Endocrinology, Diabetes and Metabolism, 030232 urology & nephrology, Pilot Projects, Diabetic nephropathy, Urine, Kidney, Severity of Illness Index, 0302 clinical medicine, Endocrinology, Fibrosis, Medicine, Diabetic Nephropathies, Renal Insufficiency, Lysophosphatidylcholine, Middle Aged, 6. Clean water, Up-Regulation, 3. Good health, medicine.anatomical_structure, Female, lipids (amino acids, peptides, and proteins), medicine.symptom, Lysophosphatidic acid, Glomerular Filtration Rate, medicine.medical_specialty, Urinary system, Nephropathy, 03 medical and health sciences, Diabetes mellitus, Internal medicine, Internal Medicine, Albuminuria, Humans, Aged, business.industry, Lysophosphatidylcholines, medicine.disease, Renal Elimination, 030104 developmental biology, Diabetes Mellitus, Type 2, Case-Control Studies, Lysophospholipids, business, Biomarkers, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Kidney disease
Abstract

International audience; Diabetic nephropathy (DN) is a major cause of chronic kidney disease that frequently leads to end stage renal failure. Lysophosphatidic acid (LPA) and lysophosphatidylcholine (LPC) are lysophospholipid mediators shown to accumulate in kidney and to promote renal inflammation and tubulo-interstitial fibrosis in diabetic rodent models. Here we assessed whether LPA and LPC were associated to the development of nephropathy in diabetic human patients. Several molecular species of LPA and LPC were quantified by LC/MS-MS in urine and plasma from type 2 diabetic patients with (cases; n=41) or without (controls, n=41) nephropathy symptoms (micro/macro-albuminuria and eGFR

Published
2017
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46. Increased urine acylcarnitines in diabetic ApoE -/- mice: Hydroxytetradecadienoylcarnitine (C14:2-OH) reflects diabetic nephropathy in a context of hyperlipidemia

Author

Joost P. Schanstra, Marion Gillet, Therese Koal, Julie Klein, Koryun Mirzoyan, Kristaps Klavins, Dimitri Marsal, Colette Denis, Jean-Sébastien Saulnier-Blache, and Jean-Loup Bascands

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Biophysics, Hyperlipidemias, Biology, Fatty acid beta-oxidation, Biochemistry, Nephropathy, Diabetic nephropathy, Mice, 03 medical and health sciences, Apolipoproteins E, 0302 clinical medicine, Carnitine, Internal medicine, Diabetes mellitus, Hyperlipidemia, medicine, Animals, Diabetic Nephropathies, Molecular Biology, Mice, Knockout, chemistry.chemical_classification, Kidney, Fatty acid, Cell Biology, medicine.disease, Up-Regulation, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, chemistry, Albuminuria, medicine.symptom, Biomarkers, 030217 neurology & neurosurgery
Abstract

Hyperlipidemia is a risk factor for initiation and progression of diabetic nephropathy but the metabolic pathways altered in the diabetic kidney in a context of hyperlipidemia remain incompletely described. Assuming that changes in urine composition reflect the alteration of renal metabolism and function, we analyzed the urine metabolite composition of diabetic (streptozotocin-treatment) and control (non diabetic) ApoE-/- mice fed a high cholesterol diet using targeted quantitative metabolomics. Urine metabolome was also compared to the plasma metabolome of the same animals. As previously shown, urine albuminuria/urine creatinine ratio (uACR) and glomerular area and plasma lipids (cholesterol, triglycerides) were more elevated in diabetic mice compared to control. After adjustment to urine creatinine, the abundance of 52 urine metabolites was significantly different in diabetic mice compared to control. Among them was a unique metabolite, C14:2-OH (3-hydroxytetradecadienoylcarnitine) that, in diabetic mice, was positively and significantly correlated with uACR, glomerular hypertrophy, blood glucose and plasma lipids. That metabolite was not detected in plasma. C14:2-OH is a long-chain acylcarnitine reminiscent of altered fatty acid beta oxidation. Other acylcarnitines, particularly the short chains C3-OH, C3-DC, C4:1, C5-DC, C5-M-DC, C5-OH that are reminiscent of altered oxidation of branched and aromatic amino acids were also exclusively detected in urine but were only correlated with plasma lipids. Finally, the renal gene expression of several enzymes involved in fatty acid and/or amino acid oxidation was significantly reduced in diabetic mice compared to control. This included the bifunctional enoyl-CoA hydratase/3-hydroxyacyl-CoA (Ehhadh) that might play a central role in C14:2-OH production. This study indicate that the development of diabetes in a context of hyperlipidemia is associated with a reduced capacity of kidney to oxidize fatty acids and amino acids with the consequence of an elevation of urinary acetylcarnitines including C14:2-OH that specifically reflects diabetic nephropathy.

Published
2017
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47. Value of Urine Peptides in Assessing Kidney and Cardiovascular Disease

Author

Justyna Siwy, Joachim Beige, Joost P. Schanstra, Stanislas Faguer, Harald Mischak, Agnieszka Latosinska, Schanstra, Joost, Mosaiques Diagnostics GmbH [Hannover, Germany], Mosaiques Diagnostics and Therapeutics AG [Hannover, Germany], Département de Néphrologie et Transplantation d'organes [CHU Toulouse], Pôle Urologie - Néphrologie - Dialyse - Transplantations - Brûlés - Chirurgie plastique - Explorations fonctionnelles et physiologiques [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Martin-Luther-University Halle-Wittenberg, Département de Néphrologie et Transplantation d'organes, Hôpital de Rangueil, and CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]

Subjects
0301 basic medicine, Urinary system, kidney disease, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Context (language use), Disease, Urine, Bioinformatics, 03 medical and health sciences, Fibrosis, cardiovascular disease, Medicine, Humans, Renal Insufficiency, Chronic, Kidney, 030102 biochemistry & molecular biology, business.industry, medicine.disease, peptide, urine, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, Cardiovascular Diseases, Biomarker (medicine), biomarker, business, Peptides, Kidney disease
Abstract

International audience; Urinary peptides gained significant attention as potential biomarkers especially in the context of kidney and cardiovascular disease. In this manuscript the recent literature since 2015 on urinary peptide investigation in human kidney and cardiovascular disease is reviewed. The technology most commonly used in this context is capillary electrophoresis coupled mass spectrometry, in part owed to the large database available and the well-defined dataspace. Several studies based on over 1000 subjects were reported in the recent past, especially examining CKD273, a classifier for assessment of chronic kidney disease based on 273 urine peptides. Interestingly, the most abundant urinary peptides are generally collagen fragments, which may have gone undetected for some time as they are typically modified via proline hydroxylation. The data available suggest that urinary peptides specifically depict inflammation and fibrosis, and may serve as a non-invasive tool to assess fibrosis, which appears to be a key driver in kidney and cardiovascular disease. The recent successful completion of the first urinary peptide guided intervention trial, PRIORITY, is expected to further spur clinical application of urinary peptidomics, aiming especially at early detection of chronic diseases, prediction of progression and prognosis of drug response. This article is protected by copyright. All rights reserved.

Published
2020
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48. Apelin affects the mouse aging urinary peptidome with minimal effects on kidney

Author

Claire, Vinel, Joost P, Schanstra, Franck, Boizard, Ophélie, Péreira, Johanna, Auriau, Alizée, Dortignac, Benjamin, Breuil, Guylène, Feuillet, Esther, Nkuipou-Kenfack, Petra, Zürbig, Philippe, Valet, Jean-Loup, Bascands, Cédric, Dray, Colette, Denis, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Mosaiques Diagnostics GmbH, Diabète athérothrombose et thérapies Réunion Océan Indien (DéTROI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de La Réunion (UR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Schanstra, Joost

Subjects
Aging, Apelin Receptors, Support Vector Machine, Proteome, [SDV]Life Sciences [q-bio], lcsh:R, lcsh:Medicine, Apoptosis, Kidney, Models, Biological, Article, Mice, Inbred C57BL, [SDV] Life Sciences [q-bio], Mice, Ageing, Autophagy, Animals, Apelin, Intercellular Signaling Peptides and Proteins, lcsh:Q, Amino Acid Sequence, RNA, Messenger, Peptides, lcsh:Science, Glomerular Filtration Rate
Abstract

International audience; Kidney function is altered by age together with a declined filtration capacity of 5-10% per decade after 35 years. Renal aging shares many characteristics with chronic kidney disease. Plasma levels of the bioactive peptide apelin also decline with age and apelin has been shown to be protective in chronic kidney disease. Therefore we evaluated whether apelin could also improve aging-induced renal lesions and function in mice. Since urine is for the major part composed of proteins and peptides originating from the kidney, we first studied apelin-induced changes, in the aging urinary peptidome. Despite the recently published age-associated plasma decrease of apelin, expression of the peptide and its receptor was increased in the kidneys of 24 months old mice. Twenty-eight days treatment with apelin significantly modified the urinary peptidome of 3 and 24 months old mice towards a signature suggesting more advanced age at 3 months, and a younger age at 24 months. The latter was accompanied by a decreased staining of collagen (Sirius red staining) in 24 months old apelin-treated mice, without changing aging-induced glomerular hypertrophy. In addition, apelin was without effect on aging-induced renal autophagy, apoptosis, inflammation and reduced renal function. In conclusion, treatment of aged mice with apelin had a limited effect on kidney lesions although modifying the urinary peptidome towards a younger signature. This supports evidence of apelin inducing more general beneficial effects on other aging organs, muscles in particular, as recently shown for sarcopenia, markers of which end up via the glomerular filtration in urine.

Published
2019
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50. Increased urinary lysophosphatidic acid in mouse with subtotal nephrectomy: potential involvement in chronic kidney disease

Author

Aude Dupuy, Julie Klein, Claire Vinel, Pierre Sicard, Dimitri Marsal, Joost P. Schanstra, Jean-Sébastien Saulnier-Blache, Colette Denis, Koryun Mirzoyan, Justine Bertrand-Michel, Anna Baïotto, and Jean-Loup Bascands

Subjects
0301 basic medicine, medicine.medical_specialty, Physiology, Urinary system, Phosphatidate Phosphatase, Down-Regulation, Gene Expression, Renal function, Nerve Tissue Proteins, Nephron, Kidney, urologic and male genital diseases, Nephrectomy, Biochemistry, Mice, 03 medical and health sciences, chemistry.chemical_compound, Internal medicine, Lysophosphatidic acid, medicine, Albuminuria, Animals, Phosphorylation, Renal Insufficiency, Chronic, Chemistry, General Medicine, medicine.disease, Fibrosis, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, Tubulointerstitial fibrosis, Nephritis, Interstitial, Female, lipids (amino acids, peptides, and proteins), Lysophospholipids, biological phenomena, cell phenomena, and immunity, medicine.symptom, Kidney disease
Abstract

Increased incidence of chronic kidney disease (CKD) with consecutive progression to end-stage renal disease represents a significant burden to healthcare systems. Renal tubulointerstitial fibrosis (TIF) is a classical hallmark of CKD and is well correlated with the loss of renal function. The bioactive lysophospholipid lysophosphatidic acid (LPA), acting through specific G-protein-coupled receptors, was previously shown to be involved in TIF development in a mouse model of unilateral ureteral obstruction. Here, we study the role of LPA in a mouse subjected to subtotal nephrectomy (SNx), a more chronic and progressive model of CKD. Five months after surgical nephron reduction, SNx mice showed massive albuminuria, extensive TIF, and glomerular hypertrophy when compared to sham-operated animals. Urinary and plasma levels of LPA were analyzed using liquid chromatography tandem mass spectrometry. LPA was significantly increased in SNx urine, not in plasma, and was significantly correlated with albuminuria and TIF. Moreover, SNx mice showed significant downregulation in the renal expression of lipid phosphate phosphohydrolases (LPP1, 2, and 3) that might be involved in reduced LPA bioavailability through dephosphorylation. We concluded that SNx increases urinary LPA through a mechanism that could involve co-excretion of plasma LPA with albumin associated with a reduction of its catabolism in the kidney. Because of the previously demonstrated profibrotic activity of LPA, the association of urinary LPA with TIF suggests the potential involvement of LPA in the development of advanced CKD in the SNx mouse model. Targeting LPA metabolism might represent an interesting approach in CKD treatment.

Published
2016
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