505 results on '"Matthias Kretzler"'
Search Results
202. ATP-binding cassette A1 deficiency causes cardiolipin-driven mitochondrial dysfunction in podocytes
- Author
-
Sandra Merscher, Matthias Kretzler, Christopher E. Pedigo, Santanu Banerjee, Mengyuan Ge, Reiko Inagi, Shaoyi Liu, Xiaochen Liu, G. Michelle Ducasa, Alessia Fornoni, Yu Ishimoto, Hazel H. Szeto, Judith Molina, Alexis Sloan, Javier Varona Santos, Flavia Fontanesi, Cyrille Maugeais, Shamroop K. Mallela, George W. Burke, Viji Nair, Alla Mitrofanova, Robert G. Nelson, Armando J. Mendez, Jin Ju Kim, and Yanio Hernandez
- Subjects
0301 basic medicine ,Oxidative phosphorylation ,Mitochondrion ,Podocyte ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Tangier disease ,medicine ,Cardiolipin ,polycyclic compounds ,Diabetes Mellitus ,Albuminuria ,Humans ,Diabetic Nephropathies ,cardiovascular diseases ,SOAT1 ,biology ,Chemistry ,Podocytes ,nutritional and metabolic diseases ,hemic and immune systems ,General Medicine ,Elamipretide ,medicine.disease ,Receptor, Insulin ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,ABCA1 ,biology.protein ,Cancer research ,lipids (amino acids, peptides, and proteins) ,Research Article ,Signal Transduction - Abstract
Fibroblasts from patients with Tangier disease carrying ATP-binding cassette A1 (ABCA1) loss-of-function mutations are characterized by cardiolipin accumulation, a mitochondrial-specific phospholipid. Suppression of ABCA1 expression occurs in glomeruli from patients with diabetic kidney disease (DKD) and in human podocytes exposed to DKD sera collected prior to the development of DKD. We demonstrated that siRNA ABCA1 knockdown in podocytes led to reduced oxygen consumption capabilities associated with alterations in the oxidative phosphorylation (OXPHOS) complexes and with cardiolipin accumulation. Podocyte-specific deletion of Abca1 (Abca1(fl/fl)) rendered mice susceptible to DKD, and pharmacological induction of ABCA1 improved established DKD. This was not mediated by free cholesterol, as genetic deletion of sterol-o-acyltransferase-1 (SOAT1) in Abca1(fl/fl) mice was sufficient to cause free cholesterol accumulation but did not cause glomerular injury. Instead, cardiolipin mediates ABCA1-dependent susceptibility to podocyte injury, as inhibition of cardiolipin peroxidation with elamipretide improved DKD in vivo and prevented ABCA1-dependent podocyte injury in vitro and in vivo. Collectively, we describe a pathway definitively linking ABCA1 deficiency to cardiolipin-driven mitochondrial dysfunction. We demonstrated that this pathway is relevant to DKD and that ABCA1 inducers or inhibitors of cardiolipin peroxidation may each represent therapeutic strategies for the treatment of established DKD.
- Published
- 2019
203. Proteomic Analysis Identifies Distinct Glomerular Extracellular Matrix in Collapsing Focal Segmental Glomerulosclerosis
- Author
-
Susan Coventry, Michelle T. Barati, Michael L. Merchant, Jack F.M. Wetzels, Kenneth R. McLeish, Laura H. Mariani, Jeroen K.J. Deegens, Michael E. Brier, Matthias Kretzler, Dawn J. Caster, Liliane Hobeika, Ilse M. Rood, Christopher P. Larsen, Jessica Hata, Daniel W. Wilkey, Ming Li, Jeffrey B. Hodgin, Jon B. Klein, and Jonathan P. Troost
- Subjects
0301 basic medicine ,Proteomics ,Pathology ,medicine.medical_specialty ,Kidney Glomerulus ,030232 urology & nephrology ,urologic and male genital diseases ,Cathepsin B ,Extracellular matrix ,03 medical and health sciences ,0302 clinical medicine ,Focal segmental glomerulosclerosis ,All institutes and research themes of the Radboud University Medical Center ,Membranous nephropathy ,Clinical Research ,medicine ,Humans ,Cathepsin ,Extracellular Matrix Proteins ,Microscopy, Confocal ,Chemistry ,urogenital system ,Glomerulosclerosis, Focal Segmental ,Glomerulosclerosis ,Epithelial Cells ,General Medicine ,medicine.disease ,Cathepsins ,Immunohistochemistry ,female genital diseases and pregnancy complications ,030104 developmental biology ,Nephrology ,Annexin A3 ,Synaptopodin ,Renal disorders Radboud Institute for Health Sciences [Radboudumc 11] - Abstract
Background The mechanisms leading to extracellular matrix (ECM) replacement of areas of glomerular capillaries in histologic variants of FSGS are unknown. This study used proteomics to test the hypothesis that glomerular ECM composition in collapsing FSGS (cFSGS) differs from that of other variants. Methods ECM proteins in glomeruli from biopsy specimens of patients with FSGS not otherwise specified (FSGS-NOS) or cFSGS and from normal controls were distinguished and quantified using mass spectrometry, verified and localized using immunohistochemistry (IHC) and confocal microscopy, and assessed for gene expression. The analysis also quantified urinary excretion of ECM proteins and peptides. Results Of 58 ECM proteins that differed in abundance between cFSGS and FSGS-NOS, 41 were more abundant in cFSGS and 17 in FSGS-NOS. IHC showed that glomerular tuft staining for cathepsin B, cathepsin C, and annexin A3 in cFSGS was significantly greater than in other FSGS variants, in minimal change disease, or in membranous nephropathy. Annexin A3 colocalized with cathepsin B and C, claudin-1, phosphorylated ERK1/2, and CD44, but not with synaptopodin, in parietal epithelial cells (PECs) infiltrating cFSGS glomeruli. Transcripts for cathepsins B and C were increased in FSGS glomeruli compared with normal controls, and urinary excretion of both cathepsins was significantly greater in cFSGS compared with FSGS-NOS. Urinary excretion of ECM-derived peptides was enhanced in cFSGS, although in silico analysis did not identify enhanced excretion of peptides derived from cathepsin B or C. Conclusions ECM differences suggest that glomerular sclerosis in cFSGS differs from that in other FSGS variants. Infiltration of activated PECs may disrupt ECM remodeling in cFSGS. These cells and their cathepsins may be therapeutic targets.
- Published
- 2019
204. The immune cell landscape in kidneys of patients with lupus nephritis
- Author
-
William F. Pendergraft, Richard A. Furie, Fan Zhang, Diane L. Kamen, Jennifer H. Anolik, Jill P. Buyon, Soumya Raychaudhuri, Yanyan Liu, Elena Massarotti, Kamil Slowikowski, Chaim Putterman, James A. Lederer, Michael B. Brenner, Arnon Arazi, Akiko Noma, Betty Diamond, Patti Tosta, Matthias Kretzler, Kenneth C. Kalunian, David A. Hildeman, Meyeon Park, Edward P. Browne, Shuqiang Li, Thomas Eisenhaure, Celine C. Berthier, David Wofsy, Anne Davidson, Paul Hoover, William Apruzzese, Chad Nusbaum, Nir Hacohen, E. Steve Woodle, Elizabeth A. McInnis, David J. Lieb, Scott Steelman, A. Helena Jonsson, Maria Dall'Era, Deepak A. Rao, Fernanda Payan-Schober, Dawn E. Smilek, Danielle Sutherby, Michelle Petri, and Adam Chicoine
- Subjects
0301 basic medicine ,Kidney Disease ,Biopsy ,Lupus nephritis ,Kidney ,Chemokine receptor ,0302 clinical medicine ,Immunophenotyping ,Interferon ,Leukocytes ,Immunology and Allergy ,Cluster Analysis ,2.1 Biological and endogenous factors ,Myeloid Cells ,Lymphocytes ,Aetiology ,Flow Cytometry ,Lupus Nephritis ,3. Good health ,Monocyte differentiation ,Single-Cell Analysis ,medicine.drug ,1.1 Normal biological development and functioning ,Accelerating Medicines Partnership in SLE network ,Immunology ,Renal and urogenital ,Lupus ,Autoimmune Disease ,03 medical and health sciences ,Immune system ,Clinical Research ,Underpinning research ,medicine ,Genetics ,Humans ,Autoimmune disease ,business.industry ,Gene Expression Profiling ,Inflammatory and immune system ,Kidney metabolism ,Computational Biology ,Epithelial Cells ,Molecular Sequence Annotation ,medicine.disease ,030104 developmental biology ,Gene Expression Regulation ,Interferons ,business ,Transcriptome ,Biomarkers ,030215 immunology - Abstract
Lupus nephritis is a potentially fatal autoimmune disease for which the current treatment is ineffective and often toxic. To develop mechanistic hypotheses of disease, we analyzed kidney samples from patients with lupus nephritis and from healthy control subjects using single-cell RNA sequencing. Our analysis revealed 21 subsets of leukocytes active in disease, including multiple populations of myeloid cells, T cells, natural killer cells and B cells that demonstrated both pro-inflammatory responses and inflammation-resolving responses. We found evidence of local activation of B cells correlated with an age-associated B-cell signature and evidence of progressive stages of monocyte differentiation within the kidney. A clear interferon response was observed in most cells. Two chemokine receptors, CXCR4 and CX3CR1, were broadly expressed, implying a potentially central role in cell trafficking. Gene expression of immune cells in urine and kidney was highly correlated, which would suggest that urine might serve as a surrogate for kidney biopsies.
- Published
- 2019
205. AB0167 SINGLE CELL RNA EXPRESSION IN LUPUS NEPHRITIS COMPARING AFRICAN-AMERICAN AND CAUCASIAN PATIENTS IDENTIFIES DIFFERENTIAL EXPRESSION OF TYPE I INTERFERON PATHWAY
- Author
-
Celine C. Berthier, Michelle Petri, Andrea Fava, Yuji Zhang, Betty Diamond, David Wofsy, David A. Hildeman, Arnon Arazi, Nir Hacohen, Anne Davidson, Deepak A. Rao, Matthias Kretzler, Michael B. Brenner, and E. Steve Woodle
- Subjects
Oncology ,medicine.medical_specialty ,education.field_of_study ,business.industry ,Population ,Lupus nephritis ,medicine.disease ,medicine.anatomical_structure ,Immune system ,Interferon ,Internal medicine ,medicine ,business ,education ,Nephritis ,CD8 ,B cell ,Biomedical sciences ,medicine.drug - Abstract
Background: African-American ethnicity is associated with a 3-fold higher risk of developing systemic lupus erythematosus (SLE). In addition, there is an increased risk of lupus nephritis (2-fold), high-risk histological features, and resistance to treatment. This may account for the increased mortality rate compared to Caucasian patients, especially in women. Objectives: In Phase One of the Accelerating Medicines Partnership (AMP) study, we used single-cell RNA sequencing on kidney biopsies from patients with active lupus nephritis to identify pathways that were differentially expressed in African-American patients. Methods: Single cell RNA sequencing was performed on renal biopsies obtained for clinical purpose for active nephritis using CEL-Seq2. Cell clusters with similar expression profile were identified using t-distributed stochastic neighbor embedding (t-SNE). First, the relative abundance of a cluster in AAs compared to Caucasian was determined using a logistic mixed model. Second, the differential expression profile was determined for each cell cluster and we applied Ingenuity Pathway Analysis (IPA) (QIAGEN Bioinformatics) to identify pathways of interest. Results: Samples from 13 AA and 7 Caucasian patients were obtained. Of the 3097 sequenced cell libraries, we used 2354 which passed our quality filter for a total of 30155 unique molecular identifiers. We identified 16 cell clusters including CD4, CD8, B and plasma cells, NK, myeloid cells, and tubular cells. We identified 2 cell clusters unique to African-American patients, a T and a B cell population with high expression of interferon inducible genes. We also identified that same cell populations may have differential gene expression profiles across ethnicity. For example, CD4 T cells in African-Americans have a higher expression of type 1 and type 2 interferon pathways. In contrast, myeloid cells have several upregulated pathways in Caucasians, including ERK/MAPK signaling. Conclusion: African-American lupus nephritis patients may have a stronger interferon pathway activation in infiltrating immune cells. Several other pathways, including ERK/MAPK, are differentially expressed in infiltrating cells based on ethnicity. These results suggest that ethnicity might predict a response to both current and upcoming treatments, paving the way for a more personalized approach to treatment in lupus nephritis. Further work in Phase 2 of AMP will confirm and extend these findings. Disclosure of Interests: Andrea Fava: None declared, Yuji Zhang: None declared, Nir Hacohen: None declared, Arnon Arazi: None declared, Celine Berthier: None declared, Deepak Rao: None declared, Michael Brenner Grant/research support from: Roche: sponsored research agreement on stromal cells (but has nothing to do with checkpoint related disease), Consultant for: GSK: consultant. (I am part of their immunology network, a group of about 8 immunologists who advise them regularly and broadly in the areas of inflammation and infection)., David Wofsy Consultant for: GlaxoSmithKline – Member, data safety monitoring board Novartis – Member, data safety monitoring board Celgene – member, scientific advisory board, Anne Davidson: None declared, Matthias Kretzler: None declared, David Hildeman: None declared, E. Steve Woodle: None declared, Betty Diamond: None declared, Michelle A Petri Shareholder of: Pfizer, Merck, Grant/research support from: AstraZeneca, Exagen, Consultant for: Eli Lilly, GSK, Merck EMD Serono, Janssen, Amgen, Novartis, Quintiles, Exagen, Inova Diagnostics, AstraZeneca, Blackrock, Glenmark, UCB, and the Annenberg Center for Health Sciences
- Published
- 2019
206. 204 The immune cell landscape in kidneys of lupus nephritis patients
- Author
-
Nir Hacohen, Betty Diamond, Arnon Arazi, Deepak A. Rao, David J. Lieb, Matthias Kretzler, Edward P. Browne, Thomas Eisenhaure, Celine C. Berthier, and Anne Davidson
- Subjects
Cell type ,Kidney ,Myeloid ,business.industry ,Lupus nephritis ,medicine.disease ,medicine.anatomical_structure ,Immune system ,Interferon ,Monocyte differentiation ,Immunology ,Medicine ,business ,B cell ,medicine.drug - Abstract
Background Lupus nephritis is a potentially fatal autoimmune disease, whose current treatment is ineffective and often toxic. In 2014, the National Institute of Health (NIH), industry and non-profit organizations joined their efforts with the AMP project, whose goal is to identify new diagnostic and therapeutic targets through a better understanding of the mechanisms by which individual cell types contribute to autoimmune tissue damage. Methods To gain insights into disease mechanisms, we analyzed kidney samples from lupus nephritis patients and healthy controls using single-cell RNA-seq. Renal biopsies from 24 LN patients and 10 pre-transplant living donors (LD) were acquired across a distributed research network using a single, uniform pipeline developed by the AMP network. In brief, biopsies were cryopreserved and shipped to a centralized processing site for tissue dissociation. A total of 3541 leukocytes and 1621 epithelial cells were sorted from LN kidney samples. 438 leukocytes and 572 epithelial cells were sorted from LD biopsies. The transcriptome of those LN single tissue-infiltrating cells were assessed using single cell RNA-seq. Results Our analysis revealed 21 subsets of leukocytes active in disease, including multiple populations of myeloid, T, NK and B cells, demonstrating both pro-inflammatory and resolving responses. We found evidence of local activation of B cells correlated with an age-associated B cell signature, and of progressive stages of monocyte differentiation within the kidney. A clear interferon response was observed in most cells. Two chemokine receptors, C×CR4 and C×3CR1, were broadly expressed, pointing to potential therapeutic targets. Gene expression of immune cells in urine and kidney was highly correlated, suggesting urine may be a surrogate for kidney biopsies. Conclusions Our results provide a first comprehensive view of the complex network of leukocytes active in lupus nephritis kidneys. Results from this Phase 1 study identified LN active cells and pathways that can be used to guide the development of novel therapies. Analyses at a bigger scale (n=200 LN) in Phase 2 will allow to correlate patterns and signatures of infiltrating cells with those of intrinsic renal cells, particularly the epithelial cells that make up 90% of renal cells and that are prone to hypoxic damage and cellular stress. It will accelerate the discovery of new therapeutic targets and identification of biomarkers to guide therapeutic decisions in LN and integrate the treatment effect. Funding Source(s): Funding was provided through grants from the National Institutes of Health (UH2-AR067676, UH2-AR067677, UH2-AR067679, UH2-AR067681, UH2-AR067685, UH2-AR067688, UH2-AR067689, UH2-AR067690, UH2-AR067691, UH2-AR067694, and UM2-AR067678).
- Published
- 2019
207. 205 Single cell RNA expression in lupus nephritis comparing african-american and caucasian patients identifies differential expression of type I interferon pathway
- Author
-
Michael B. Brenner, Deepak A. Rao, Yuji Zhang, David A. Hildeman, Celine C. Berthier, David Wofsy, Matthias Kretzler, Michelle Petri, E. Steve Woodle, Betty Diamond, Nir Hacohen, Anne Davidson, Andrea Fava, and Arnon Arazi
- Subjects
education.field_of_study ,business.industry ,Population ,Cell ,Lupus nephritis ,medicine.disease ,medicine.anatomical_structure ,Immune system ,Interferon ,Immunology ,medicine ,business ,education ,Nephritis ,B cell ,CD8 ,medicine.drug - Abstract
Background African-American ethnicity is associated with a 3-fold higher risk of developing systemic lupus erythematosus (SLE). In addition, there is an increased risk of lupus nephritis (2-fold), high-risk histological features, and resistance to treatment. This may account for the increased mortality rate compared to Caucasian patients, especially in women. In Phase One of the Accelerating Medicines Partnership (AMP) study, we used single-cell RNA sequencing on kidney biopsies from patients with active lupus nephritis to identify pathways that were differentially expressed in African-American patients. Methods Single cell RNA sequencing was performed on renal biopsies obtained for clinical purpose for active nephritis using CEL-Seq2. Cell clusters with similar expression profile were identified using t-distributed stochastic neighbor embedding (t-SNE). First, the relative abundance of a cluster in AAs compared to Caucasian was determined using a logistic mixed model. Second, the differential expression profile was determined for each cell cluster and we applied Ingenuity Pathway Analysis (IPA) (QIAGEN Bioinformatics) to identify pathways of interest. Results Samples from 13 AA and 7 Caucasian patients were obtained. Of the 3097 sequenced cell libraries, we used 2354 which passed our quality filter for a total of 30 155 unique molecular identifiers. We identified 16 cell clusters including CD4, CD8, B and plasma cells, NK, myeloid cells, and tubular cells. We identified 2 cell clusters unique to African-American patients, a T and a B cell population with high expression of interferon inducible genes. We also identified that same cell populations may have differential gene expression profiles across ethnicity. For example, CD4 T cells in African-Americans have a higher expression of type 1 and type 2 interferon pathways. In contrast, myeloid cells have several upregulated pathways in Caucasians, including ERK/MAPK signaling. Conclusions African-American lupus nephritis patients may have a stronger interferon pathway activation in infiltrating immune cells. Several other pathways, including ERK/MAPK, are differentially expressed in infiltrating cells based on ethnicity. These results suggest that ethnicity might predict a response to both current and upcoming treatments, paving the way for a more personalized approach to treatment in lupus nephritis. Further work in Phase 2 of AMP will confirm and extend these findings. Funding Source(s): NIH foundation partnership with AbbVie, Biogen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Johnson and Johnson, Lilly, Merck, Pfizer, Sanofi, Takeda, and Verily.
- Published
- 2019
208. Proteome Analysis of Isolated Podocytes Reveals Stress Responses in Glomerular Sclerosis
- Author
-
Alexander Kuczkowski, Matthias Kretzler, Paul T. Brinkkoetter, Sean Eddy, Jörg Höhfeld, Martin Hoehne, Lucas Kuehne, Markus M. Rinschen, Bernhard Schermer, Thomas Benzing, Sybille Koehler, Florian Grahammer, Bodo B. Beck, and Christian Jüngst
- Subjects
Proteomics ,Filamins ,Biology ,Filamin ,urologic and male genital diseases ,Podocyte ,Transcriptome ,Mice ,Random Allocation ,Stress, Physiological ,medicine ,Animals ,Humans ,Cells, Cultured ,urogenital system ,Glomerulosclerosis, Focal Segmental ,Podocytes ,Glomerulosclerosis ,General Medicine ,medicine.disease ,Cell biology ,Rats ,Disease Models, Animal ,Proteinuria ,Proteostasis ,medicine.anatomical_structure ,Basic Research ,Gene Expression Regulation ,Nephrology ,Proteome ,Slit diaphragm - Abstract
Background Understanding podocyte-specific responses to injury at a systems level is difficult because injury leads to podocyte loss or an increase of extracellular matrix, altering glomerular cellular composition. Finding a window into early podocyte injury might help identify molecular pathways involved in the podocyte stress response. Methods We developed an approach to apply proteome analysis to very small samples of purified podocyte fractions. To examine podocytes in early disease states in FSGS mouse models, we used podocyte fractions isolated from individual mice after chemical induction of glomerular disease (with Doxorubicin or LPS). We also applied single-glomerular proteome analysis to tissue from patients with FSGS. Results Transcriptome and proteome analysis of glomeruli from patients with FSGS revealed an underrepresentation of podocyte-specific genes and proteins in late-stage disease. Proteome analysis of purified podocyte fractions from FSGS mouse models showed an early stress response that includes perturbations of metabolic, mechanical, and proteostasis proteins. Additional analysis revealed a high correlation between the amount of proteinuria and expression levels of the mechanosensor protein Filamin-B. Increased expression of Filamin-B in podocytes in biopsy samples from patients with FSGS, in single glomeruli from proteinuric rats, and in podocytes undergoing mechanical stress suggests that this protein has a role in detrimental stress responses. In Drosophila, nephrocytes with reduced filamin homolog Cher displayed altered filtration capacity, but exhibited no change in slit diaphragm structure. Conclusions We identified conserved mechanisms of the podocyte stress response through ultrasensitive proteome analysis of human glomerular FSGS tissue and purified native mouse podocytes during early disease stages. This approach enables systematic comparisons of large-scale proteomics data and phenotype-to-protein correlation.
- Published
- 2019
209. Identification of dicarbonyl and L-xylulose reductase as a therapeutic target in human chronic kidney disease
- Author
-
Julia Kerschbaum, Paul Perco, Gert Mayer, Catherine Zhu, Rajasree Menon, Johannes Leierer, Wenjun Ju, Matthias Kretzler, and Michael A. Rudnicki
- Subjects
0301 basic medicine ,Nephrology ,Adult ,Male ,medicine.medical_specialty ,Renal function ,Context (language use) ,Pharmacology ,urologic and male genital diseases ,Kidney ,Protective Agents ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Empagliflozin ,Humans ,Renal Insufficiency, Chronic ,L-xylulose reductase ,Canagliflozin ,business.industry ,General Medicine ,Middle Aged ,medicine.disease ,3. Good health ,030104 developmental biology ,Treatment Outcome ,030220 oncology & carcinogenesis ,Disease Progression ,Female ,business ,Transcriptome ,Nephrotic syndrome ,Kidney disease ,medicine.drug ,Follow-Up Studies ,Sugar Alcohol Dehydrogenases ,Research Article - Abstract
An imbalance of nephroprotective factors and renal damaging molecules contributes to development and progression of chronic kidney disease (CKD). We investigated associations of renoprotective factor gene expression patterns with CKD severity and outcome. Gene expression profiles of 197 previously reported renoprotective factors were analyzed in a discovery cohort in renal biopsies of 63 CKD patients. Downregulation of dicarbonyl and L-xylulose reductase (DCXR) showed the strongest association with disease progression. This significant association was validated in an independent set of 225 patients with nephrotic syndrome from the multicenter NEPTUNE cohort. Reduced expression of DCXR was significantly associated with degree of histological damage as well as with lower estimated glomerular filtration rate and increased urinary protein levels. DCXR downregulation in CKD was confirmed in 3 publicly available transcriptomics data sets in the context of CKD. Expression of DCXR showed positive correlations to enzymes that are involved in dicarbonyl stress detoxification based on transcriptomics profiles. The sodium glucose cotransporter-2 (SGLT2) inhibitors canagliflozin and empagliflozin showed a beneficial effect on renal proximal tubular cells under diabetic stimuli-enhanced DCXR gene expression. In summary, lower expression of the renoprotective factor DCXR in renal tissue is associated with more severe disease and worse outcome in human CKD.
- Published
- 2019
210. Serum amyloid A and Janus kinase 2 in a mouse model of diabetic kidney disease
- Author
-
Hongyu Zhang, Katherine R. Tuttle, Rick L. Meek, Frank C. Brosius, Sheryl K. Cooney, Robert J. Anderberg, Brad P. Dieter, Jen L. Bergin, Matthias Kretzler, and Viji Nair
- Subjects
0301 basic medicine ,Immunostaining ,030204 cardiovascular system & hematology ,Pathology and Laboratory Medicine ,Kidney ,Biochemistry ,Podocyte ,Gene Knockout Techniques ,Mice ,0302 clinical medicine ,Endocrinology ,hemic and lymphatic diseases ,Medicine and Health Sciences ,Diabetic Nephropathies ,Enzyme-Linked Immunoassays ,Post-Translational Modification ,Phosphorylation ,Immune Response ,Cells, Cultured ,2. Zero hunger ,Staining ,Multidisciplinary ,Janus kinase 2 ,biology ,Podocytes ,Animal Models ,medicine.anatomical_structure ,Cholesterol ,Experimental Organism Systems ,Medicine ,medicine.symptom ,Anatomy ,Glomeruli ,Research Article ,Signal Transduction ,medicine.medical_specialty ,Endocrine Disorders ,Science ,Immunology ,Inflammation ,Mouse Models ,Research and Analysis Methods ,03 medical and health sciences ,Model Organisms ,Signs and Symptoms ,Diagnostic Medicine ,Internal medicine ,Diabetes mellitus ,medicine ,Diabetes Mellitus ,Animals ,Serum amyloid A ,Immunoassays ,Protein Kinase Inhibitors ,Triglycerides ,Glycated Hemoglobin ,Serum Amyloid A Protein ,business.industry ,Glomerulosclerosis ,Kidney metabolism ,Biology and Life Sciences ,Proteins ,Kidneys ,Renal System ,Janus Kinase 1 ,Janus Kinase 2 ,medicine.disease ,Angiotensin II ,030104 developmental biology ,Specimen Preparation and Treatment ,Metabolic Disorders ,biology.protein ,Animal Studies ,Immunologic Techniques ,business - Abstract
BackgroundSerum amyloid A (SAA), a potent inflammatory mediator, and Janus kinase 2 (JAK2), an intracellular signaling kinase, are increased by diabetes. The aims were to elucidate: 1) a JAK2-mediated pathway for increased SAA in the kidneys of diabetic mice; 2) a JAK2-SAA pathway for inflammation in podocytes.MethodsAkita diabetic mice (129S6) with podocyte JAK2 overexpression and angiotensin II infusion (4 weeks) were given a JAK1,2 inhibitor (LY03103801, 3 mg/kg/day orally for the last two weeks). Kidneys were immunostained for SAA isoform 3 (SAA3). SAA3 knockout and control mouse podocytes were exposed to advanced glycation end products (AGE) or exogenous SAA with JAK2 inhibition (Tyrphostin AG 490, 50μM). JAK2 activity (phosphorylation, Western blot, 1 hour) and mRNA for SAA3 and associated inflammatory genes (Cxcl5, Ccl2, and Ccl5) were measured by RT-PCR (20 hours).ResultsSAA3 protein was present throughout the diabetic kidney, and podocyte JAK2 overexpression increased tubulointerstitial SAA3 compared to wild type diabetic controls, 43% versus 14% (p = 0.007); JAK1,2 inhibition attenuated the increase in SAA3 to 15% (p = 0.003). Urine albumin-to-creatinine ratio (r = 0.49, p = 0.03), mesangial index (r = 0.64, p = 0.001), and glomerulosclerosis score (r = 0.51, p = 0.02) were associated with SAA3 immunostaining scores across mouse groups. Exposing podocytes to AGE or exogenous SAA increased JAK2 activity within one hour and mRNA for associated inflammatory genes after 20 hours. JAK2 inhibition reduced SAA3 mRNA expression in podocytes exposed to AGE or SAA. SAA3 knockout podocytes had >85% lower AGE-induced inflammatory genes.ConclusionJAK1,2 inhibition reduced SAA and histological features of DKD in podocyte JAK2-overexpressing mice. In podocytes exposed to a diabetes-like condition, JAK2 inhibition reduced expression of SAA, while SAA knockout blocked expression of associated pro-inflammatory mediators. SAA may promote JAK2-dependent inflammation in the diabetic kidney.
- Published
- 2019
211. Strategies to improve monitoring disease progression, assessing cardiovascular risk, and defining prognostic biomarkers in chronic kidney disease
- Author
-
Sanjay K. Agarwal, Ernest Kiswaya Sumaili, Michelle J Pena, Ziad A. Massy, Harold I. Feldman, David Harris, Laura Sola, Ron T. Gansevoort, Andrzej Wiecek, Hiddo J.L. Heerspink, Robert G. Nelson, Agnes B. Fogo, Charlotte Roberts, Zhihong Liu, Sajja Tatiyanupanwong, Josef Coresh, Vivekanand Jha, Bernadette Thomas, Gregorio T. Obrador, Matthias Kretzler, Valerie A. Luyckx, Ravindra L. Mehta, Dwomoa Adu, Chirag R. Parikh, Donal O'Donoghue, Peter Stenvinkel, University of Zurich, and Heerspink, Hiddo J L
- Subjects
Nephrology ,medicine.medical_specialty ,Population ,030232 urology & nephrology ,review ,TYPE-2 DIABETES-MELLITUS ,Renal function ,Context (language use) ,610 Medicine & health ,030204 cardiovascular system & hematology ,urologic and male genital diseases ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,CKD ,medicine ,Intensive care medicine ,Adverse effect ,education ,POPULATION ,education.field_of_study ,2727 Nephrology ,cardiovascular disease prevention ,ALBUMINURIA CHANGES ,business.industry ,MORTALITY ,Public health ,STAGE RENAL-DISEASE ,renal disease progression ,ASSOCIATION ,GLOBAL BURDEN ,novel biomarkers ,medicine.disease ,female genital diseases and pregnancy complications ,monitoring ,PREDICT ESRD ,COLLABORATIVE METAANALYSIS ,Albuminuria ,10222 Institute of Biomedical Ethics and History of Medicine ,medicine.symptom ,business ,chronic kidney disease ,Kidney disease - Abstract
Chronic kidney disease (CKD) is a major global public health problem with significant gaps in research, care, and policy. In order to mitigate the risks and adverse effects of CKD, the International Society of Nephrology has created a cohesive set of activities to improve the global outcomes of people living with CKD. Improving monitoring of renal disease progression can be done by screening and monitoring albuminuria and estimated glomerular filtration rate in primary care. Consensus on how many times and how often albuminuria and estimated glomerular filtration rate are measured should be defined. Meaningful changes in both renal biomarkers should be determined in order to ascertain what is clinically relevant. Increasing social awareness of CKD and partnering with the technological community may be ways to engage patients. Furthermore, improving the prediction of cardiovascular events in patients with CKD can be achieved by including the renal risk markers albuminuria and estimated glomerular filtration rate in cardiovascular risk algorithms and by encouraging uptake of assessing cardiovascular risk by general practitioners and nephrologists. Finally, examining ways to further validate and implement novel biomarkers for CKD will help mitigate the global problem of CKD. The more frequent use of renal biopsy will facilitate further knowledge into the underlying etiologies of CKD and help put new biomarkers into biological context. Real-world assessments of these biomarkers in existing cohorts is important, as well as obtaining regulatory approval to use these biomarkers in clinical practice. Collaborations among academia, physician and patient groups, industry, payer organizations, and regulatory authorities will help improve the global outcomes of people living with CKD. Copyright (C) 2017, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
- Published
- 2019
212. Genetic and environmental risk factors for chronic kidney disease
- Author
-
Robyn G Langham, Chih-Wei Yang, Masaomi Nangaku, Matthias Kretzler, Gregorio T. Obrador, Robert J. Walker, Ulla T. Schultheiss, Carol A. Pollock, Caroline S. Fox, Ricardo Correa-Rotter, Peter Stenvinkel, Roberto Pecoits-Filho, Anna Köttgen, and Jerome Rossert
- Subjects
0301 basic medicine ,medicine.medical_specialty ,030232 urology & nephrology ,review ,Renal function ,Genome-wide association study ,Pharmacology ,Biology ,medicine.disease ,Public health care ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Environmental risk ,Nephrology ,medicine ,Identification (biology) ,Intensive care medicine ,Kidney disease - Abstract
In order to change the current state of chronic kidney disease knowledge and therapeutics, a fundamental improvement in the understanding of genetic and environmental causes of chronic kidney disease is essential. This article first provides an overview of the existing knowledge gaps in our understanding of the genetic and environmental causes of chronic kidney disease, as well as their interactions. The second part of the article formulates goals that should be achieved in order to close these gaps, along with suggested timelines and stakeholders that are to be involved. A better understanding of genetic and environmental factors and their interactions that influence kidney function in healthy and diseased conditions can provide novel insights into renal physiology and pathophysiology and result in the identification of novel therapeutic or preventive targets to tackle the global public health care problem of chronic kidney disease.
- Published
- 2019
213. Genome-Wide Association Study of Diabetic Kidney Disease Highlights Biology Involved in Glomerular Basement Membrane Collagen
- Author
-
Emma Ahlqvist, Catherine Godson, Darrell Andrews, Per-Henrik Groop, Raimund Weitgasser, Andrzej S. Krolewski, Kristine E. Lee, Lina Radzeviciene, Stuart J. McGurnaghan, Colin N. A. Palmer, Joanne B. Cole, Shelley B. Bull, Andrew P. Boright, Lars Stechemesser, Katalin Susztak, Barbara E.K. Klein, Wei-Min Chen, Kerstin Brismar, Carol Forsblom, Jani K. Haukka, Beata Gyorgy, Adam M. Smiles, Jose C. Florez, Harvest F. Gu, Niina Sandholm, Leif Groop, Gareth J. McKay, Maria Hughes, Mark I. McCarthy, Joel N. Hirschhorn, Athina Spiliopoulou, Michael Mauer, Samy Hadjadj, Nicolae Mircea Panduru, Helen M. Colhoun, Jingchuan Guo, Robert G. Nelson, Matthias Kretzler, Valdis Pīrāgs, Marcus G. Pezzolesi, Tarunveer S. Ahluwalia, Rasa Verkauskiene, Michel Marre, Linda T. Hiraki, Janet K. Snell-Bergeon, Bernhard Paulweber, Stephen S. Rich, Erkka Valo, Chen Di Liao, David M. Maahs, Vita Rovīte, Rachel G. Miller, Eoin P. Brennan, Peter Rossing, Natalie R. van Zuydam, Maria Luiza Caramori, Jan Skupien, Rany M. Salem, A. Peter Maxwell, Paul M. McKeigue, Maria Lajer, Gianpaolo Zerbini, Chengxiang Qiu, David-Alexandre Trégouët, Henrik Falhammar, Jennifer Todd, Rajasree Menon, Jelizaveta Sokolovska, Valma Harjutsalo, Anna Möllsten, Ronald Klein, Xiaoyu Gao, Viji Nair, Jihwan Park, Amy Jayne McKnight, Jing Jing Cao, Silvia Maestroni, Edita Prakapiene, Ian H. de Boer, Finian Martin, Andrew D. Paterson, Suna Onengut-Gumuscu, Ross Doyle, Hyun Min Kang, Angelo J. Canty, Andrew C. Liu, Tina Costacou, Carine M. Boustany-Kari, Medicum, HUS Abdominal Center, Research Programs Unit, Nefrologian yksikkö, University of Helsinki, CAMM - Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, Institute for Molecular Medicine Finland, Clinicum, Centre of Excellence in Complex Disease Genetics, University Management, Department of Medicine, and Per Henrik Groop / Principal Investigator
- Subjects
Collagen Type IV ,Male ,0301 basic medicine ,EXPRESSION ,NEPHROPATHY ,030232 urology & nephrology ,PROTEIN ,Genome-wide association study ,RECEPTOR TYROSINE KINASES ,Biology ,SUSCEPTIBILITY ,Bioinformatics ,urologic and male genital diseases ,Autoantigens ,Nephropathy ,End stage renal disease ,Cohort Studies ,Diabetic nephropathy ,03 medical and health sciences ,0302 clinical medicine ,SDG 3 - Good Health and Well-being ,Diabetes mellitus ,Glomerular Basement Membrane ,medicine ,Humans ,Diabetic Nephropathies ,Alport syndrome ,Letter to the Editor ,COMPLICATIONS ,NITRIC-OXIDE ,MUTATIONS ,1184 Genetics, developmental biology, physiology ,General Medicine ,medicine.disease ,GENE ,3. Good health ,Diabetes Mellitus, Type 1 ,030104 developmental biology ,Nephrology ,3121 General medicine, internal medicine and other clinical medicine ,Mutation ,Albuminuria ,Female ,3111 Biomedicine ,medicine.symptom ,COLLECTIN 11 CL-11 ,Genome-Wide Association Study ,Kidney disease - Abstract
BACKGROUND: Although diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown.METHODS: To identify genetic variants predisposing to diabetic kidney disease, we performed genome-wide association study (GWAS) analyses. Through collaboration with the Diabetes Nephropathy Collaborative Research Initiative, we assembled a large collection of type 1 diabetes cohorts with harmonized diabetic kidney disease phenotypes. We used a spectrum of ten diabetic kidney disease definitions based on albuminuria and renal function.RESULTS: Our GWAS meta-analysis included association results for up to 19,406 individuals of European descent with type 1 diabetes. We identified 16 genome-wide significant risk loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain (COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM). Mutations in COL4A3 are implicated in heritable nephropathies, including the progressive inherited nephropathy Alport syndrome. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of diabetic kidney disease, including albuminuria and ESKD, and demonstrated a significant association with GBM width; protective allele carriers had thinner GBM before any signs of kidney disease, and its effect was dependent on glycemia. Three other loci are in or near genes with known or suggestive involvement in this condition (BMP7) or renal biology (COLEC11 and DDR1).CONCLUSIONS: The 16 diabetic kidney disease-associated loci may provide novel insights into the pathogenesis of this condition and help identify potential biologic targets for prevention and treatment.
- Published
- 2019
214. A signature of circulating inflammatory proteins and development of end-stage renal disease in diabetes
- Author
-
Pierre-Jean Saulnier, Jihwan Park, Katalin Susztak, Zaipul I. Md Dom, Alessandro Doria, Monika A. Niewczas, Carl F. Ware, Kevin L. Duffin, Jonathan M. Wilson, Andrew Schlafly, Robert G. Nelson, Meda E. Pavkov, Jan Skupien, Paolo Fiorina, Hetal Shah, Adam M. Smiles, Jennifer K. Sun, Christopher A Simeone, Chengxiang Qiu, Helen C. Looker, Eiichiro Satake, Matthias Kretzler, Andrzej S. Krolewski, and Viji Nair
- Subjects
0301 basic medicine ,Kidney ,business.industry ,Inflammation ,General Medicine ,Type 2 diabetes ,Disease ,medicine.disease ,General Biochemistry, Genetics and Molecular Biology ,Article ,3. Good health ,End stage renal disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Diabetes mellitus ,Immunology ,medicine ,Tumor necrosis factor alpha ,medicine.symptom ,Prospective cohort study ,business - Abstract
Chronic inflammation is postulated to be involved in development of end stage renal disease (ESRD) in diabetes, but which specific circulating inflammatory proteins contribute to this risk remains unknown. To study this we examined 194 circulating inflammatory proteins in subjects from three independent cohorts with Type 1 and Type 2 diabetes. In each cohort we identified an extremely robust Kidney Risk Inflammatory Signature (KRIS) consisting of 17 novel proteins enriched for TNF Receptor Superfamily members that was associated with a 10-year risk of ESRD. All these proteins had a systemic, non-kidney source. Our prospective study findings provide strong evidence that KRIS proteins contribute to the inflammatory process underlying ESRD development in both types of diabetes. These proteins may be used as new therapeutic targets, new prognostic tests for high risk of ESRD and as surrogate outcome measures where changes in KRIS levels during intervention can reflect the tested therapy’s effectiveness., One Sentence Summary: Proteomic profiling of circulating proteins in subjects from three independent cohorts with type 1 and type 2 diabetes, identified an extremely robust inflammatory signature, consisting of 17 proteins enriched for TNF Receptor Superfamily members that was associated with a 10-year risk of end-stage renal disease.
- Published
- 2019
215. Genome-wide association study of diabetic kidney disease highlights biology involved in renal basement membrane collagen
- Author
-
Jihwan Park, Angelo J. Canty, Robert G. Nelson, Vita Rovīte, Anna Möllsten, Peter Rossing, Linda T Hiraki, Katalin Susztak, Ronald Klein, Shelley B. Bull, Jan Skupien, Jani K. Haukka, Andrew D. Paterson, Niina Sandholm, Catherine Godson, Athina Spiliopoulou, A. Peter Maxwell, Suna Onengut-Gumuscu, Tina Costacou, Harvest F. Gu, Andrew P. Boright, Barbara E.K. Klein, Rany M. Salem, David-Alexandre Trégouët, Carine M. Boustany-Kari, Lina Radzeviciene, Ross Doyle, Valma Harjutsalo, Hyun Min Kang, Gareth J. McKay, Rachel G. Miller, Jose C. Florez, Jennifer N. Todd, Maria Luiza Caramori, Leif Groop, Eoin P. Brennan, Andrzej Krolewski, Maria Lajer, Rajasree Menon, Jelizaveta Sokolovska, Michel Marre, Darrel Andrews, Dcct, Wei-Min Chen, Emma Ahlqvist, Maria Hughes, Raimund Weitgasser, Andrew S.K. Liu, Jingchuan Guo, Edita Prakapiene, Viji Nair, Matthias Kretzler, Bernhard Paulweber, Chen Di Liao, Ian H. de Boer, Jing Jing Cao, Valdis Pīrāgs, Gianpaolo Zerbini, Mark I. McCarthy, Stephen S. Rich, Tarunveer S. Ahluwalia, Janet K. Snell-Bergeon, Joel N. Hirschhorn, Colin N. A. Palmer, F Martin, Kerstin Brismar, Beata Gyorgy, Adam M. Smiles, David M. Maahs, Michael Mauer, Kristine E. Lee, Joanne B. Cole, Per-Henrik Groop, Rasa Verkauskiene, Marcus G. Pezzolesi, Xiaoyu Gao, Paul M. McKeigue, Henrik Falhammar, Stuart J. McGurnaghan, Erkka Valo, Silvia Maeastroni, Lars Stechemesser, Helen M. Colhoun, Natalie R. van Zuydam, Amy J. McKnight, Chengxiang Qiu, Carol Forsblom, Nicolae Mircea Panduru, and Samy Hadjadj
- Subjects
0303 health sciences ,Glomerular basement membrane ,Renal function ,030209 endocrinology & metabolism ,Genome-wide association study ,Biology ,urologic and male genital diseases ,medicine.disease ,Bioinformatics ,3. Good health ,Minor allele frequency ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Diabetes mellitus ,Albuminuria ,medicine ,Missense mutation ,medicine.symptom ,030304 developmental biology - Abstract
Diabetic kidney disease (DKD) is a heritable but poorly understood complication of diabetes. To identify genetic variants predisposing to DKD, we performed genome-wide association analyses in 19,406 individuals with type 1 diabetes (T1D) using a spectrum of DKD definitions basedon albuminuria and renal function. We identified 16 genome-wide significant loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain(COL4A3)gene, which encodes a major structural component of the glomerular basement membrane (GBM) implicated in heritable nephropathies. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of DKD, including albuminuria and end-stage renal disease. Three other loci are in or near genes with known or suggestive involvement in DKD(BMP7)or renal biology (COLEC11andDDR1). The 16 DKD-associated loci provide novel insights into the pathogenesis of DKD, identifying potential biological targets for prevention and treatment.
- Published
- 2018
216. Tyro3 is a podocyte protective factor in glomerular disease
- Author
-
Hongyu Chen, Zhihong Liu, Matthias Kretzler, John Cijiang He, Liwen Zhang, Zhaohong Chen, Yifan Xie, Robert G. Nelson, Viji Nair, Zhengzhe Li, Kyung Lee, Wenjun Ju, Fang Zhong, Aihua Zhang, and Yongjun Wang
- Subjects
Adult ,Male ,Transcriptional Activation ,0301 basic medicine ,Kidney Glomerulus ,urologic and male genital diseases ,Diabetes Mellitus, Experimental ,Nephropathy ,Podocyte ,Mice ,03 medical and health sciences ,Focal segmental glomerulosclerosis ,medicine ,Animals ,Humans ,Diabetic Nephropathies ,AIDS-Associated Nephropathy ,Receptor ,Protein kinase B ,Zebrafish ,Gene knockdown ,Podocytes ,urogenital system ,business.industry ,Receptor Protein-Tyrosine Kinases ,General Medicine ,Protective Factors ,medicine.disease ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Doxorubicin ,Gene Knockdown Techniques ,Glomerular Filtration Barrier ,Albuminuria ,Cancer research ,medicine.symptom ,business ,Research Article - Abstract
Our previous work demonstrated a protective role of protein S in early diabetic kidney disease (DKD). Protein S exerts antiinflammatory and antiapoptotic effects through the activation of TYRO3, AXL, and MER (TAM) receptors. Among the 3 TAM receptors, we showed that the biological effects of protein S were mediated largely by TYRO3 in diabetic kidneys. Our data now show that TYRO3 mRNA expression is highly enriched in human glomeruli and that TYRO3 protein is expressed in podocytes. Interestingly, glomerular TYRO3 mRNA expression increased in mild DKD but was suppressed in progressive DKD, as well as in focal segmental glomerulosclerosis (FSGS). Functionally, morpholino-mediated knockdown of tyro3 altered glomerular filtration barrier development in zebrafish larvae, and genetic ablation of Tyro3 in murine models of DKD and Adriamycin-induced nephropathy (ADRN) worsened albuminuria and glomerular injury. Conversely, the induction of TYRO3 overexpression specifically in podocytes significantly attenuated albuminuria and kidney injury in mice with DKD, ADRN, and HIV-associated nephropathy (HIVAN). Mechanistically, TYRO3 expression was suppressed by activation of TNF-α/NF-κB pathway, which may contribute to decreased TYRO3 expression in progressive DKD and FSGS, and TYRO3 signaling conferred antiapoptotic effects through the activation of AKT in podocytes. In conclusion, TYRO3 plays a critical role in maintaining normal podocyte function and may be a potential new drug target to treat glomerular diseases.
- Published
- 2018
217. CureGN Study Rationale, Design, and Methods: Establishing a Large Prospective Observational Study of Glomerular Disease
- Author
-
Laura H. Mariani, Andrew S. Bomback, Pietro A. Canetta, Michael F. Flessner, Margaret Helmuth, Michelle A. Hladunewich, Jonathan J. Hogan, Krzysztof Kiryluk, Patrick H. Nachman, Cynthia C. Nast, Michelle N. Rheault, Dana V. Rizk, Howard Trachtman, Scott E. Wenderfer, Corinna Bowers, Peg Hill-Callahan, Maddalena Marasa, Caroline J. Poulton, Adelaide Revell, Suzanne Vento, Laura Barisoni, Dan Cattran, Vivette D’Agati, J. Charles Jennette, Jon B. Klein, Louis-Philippe Laurin, Katherine Twombley, Ronald J. Falk, Ali G. Gharavi, Brenda W. Gillespie, Debbie S. Gipson, Larry A. Greenbaum, Lawrence B. Holzman, Matthias Kretzler, Bruce Robinson, William E. Smoyer, Lisa M. Guay-Woodford, Wooin Ahn, Gerald B. Appel, Revekka Babayev, Ibrahim Batal, Eric Brown, Eric S. Campenot, Pietro Canetta, Lucrezia Carlassara, Brenda Chan, Debanjana Chatterjee, Vivette D. D’Agati, Elisa Delbarba, Samriti Dogra, Hilda Fernandez, Bartosz Foroncewicz, Gian Marco Ghiggeri, William H. Hines, S. Ali Husain, Namrata G. Jain, Pascale Khairallah, Byum Hee Kil, Anushya Jeyabalan, Wai L. Lau, Fangming Lin, Francesca Lugani, Glen Markowitz, Sumit Mohan, Xueru Mu, Krzysztof Mucha, Thomas L. Nickolas, Stacy Piva, Jai Radhakrishnan, Maya K. Rao, Renu Regunathan-Shenk, Simone Sanna-Cherchi, Dominick Santoriello, Shayan Shirazian, Michael B. Stokes, Natalie Yu, Anthony M. Valeri, Ronald Zviti, Amira Al-Uzri, Josephine Ambruzs, Isa Ashoor, Diego Aviles, Rossana Baracco, John Barcia, Sharon Bartosh, Craig Belsha, Michael C. Braun, Yi Cai, Vladimir Chernitskiy, Aftab Chishti, Donna Claes, Kira Clark, Carl Cramer, Keefe Davis, Amy Dutcher, Elif Erkan, Daniel Feig, Michael Freundlich, Joseph Gaut, Rasheed Gbadegesin, Melisha Hanna, Guillermo Hidalgo, David Hooper, Tracy E. Hunley, Amrish Jain, Mahmoud Kallash, Margo Kamel, Myda Khalid, Theresa Kump, Jerome C. Lane, Helen Liapis, John Mahan, Nisha Mathews, Carla Nester, Cynthia Pan, Larry Patterson, Hiren Patel, Alice Raad, Cynthia Silva, Rajasree Sreedharan, Tarak Srivastava, Julia Steinke, Susan Sumner, Tetyana L. Vasylyeva, Chia-shi Wang, Donald J. Weaver, Craig S. Wong, Hong Yin, Anand Achanti, Salem Almaani, Isabelle Ayoub, Milos Budisavljevic, Maggie D'Angelo, Vimal Derebail, Huma Fatima, Ronald Falk, Agnes Fogo, Keisha Gibson, Dorey Glenn, Susan Hogan, Koyal Jain, Bruce Julian, Jason Kidd, H. Davis Massey, Amy Mottl, Shannon Murphy, Tibor Nadasdy, Jan Novak, Samir Parikh, Caroline Poulton, Thomas Brian Powell, Bryce Reeve, Matthew Renfrow, Monica Reynolds, Dana Rizk, Brad Rovin, Virginie Royal, Manish Saha, Neil Sanghani, Sally Self, Sharon Adler, Nada Alachkar, Charles Alpers, Raed Bou Matar, Carmen Avila-Casado, Serena Bagnasco, Emily Brede, Elizabeth Brown, Daniel Cattran, Michael Choi, Gabriel Contreras, Katherine M. Dell, Darren Dewalt, Michelle Denburg, Ram Dukkipati, Fernando C. Fervenza, Alessia Fornoni, Crystal Gadegbeku, Patrick Gipson, Anny Gonzalez-Zea, Leah Hasely, Elizabeth Hendren, Sangeeta Hingorani, Michelle Hladunewich, Jonathan Hogan, Jean Hou, J. Ashley Jefferson, Kenar Jhaveri, Duncan B. Johnstone, Frederick Kaskel, Amy Kogan, Jeffrey Kopp, Richard Lafayette, Kevin V. Lemley, Laura Malaga-Dieguez, Kevin Meyers, Alicia Neu, Michelle Marie O'Shaughnessy, John F. O’Toole, Andrea Oliverio, Matthew Palmer, Rulan Parekh, Renee Pitter, Heather Reich, Kimberly Reidy, Helbert Rondon, Kamalanathan K. Sambandam, Matthew Sampson, John R. Sedor, David T. Selewski, Christine B. Sethna, Jeffrey Schelling, John C. Sperati, Agnes Swiatecka-Urban, Katherine R. Tuttle, Meryl Waldman, Joseph Weisstuch, Roger Wiggins, David Williams, Cheryl Winkler, Eric Young, Olga Zhdanova, Charlotte Beil, Richard Eikstadt, Brenda Gillespie, John Graff, Stephen Hewitt, Emily Herreshoff, Chrysta Lienczewski, Sarah Mansfield, Laura Mariani, Keith McCullough, Nicholas Moore, Bruce M. Robinson, Melissa Sexton, Jonathan Troost, Matthew Wladkowski, Jarcy Zee, and Dawn Zinsser
- Subjects
Adult ,Male ,medicine.medical_specialty ,Henoch-Schonlein purpura ,Adolescent ,030232 urology & nephrology ,Disease ,Glomerulonephritis, Membranous ,Risk Assessment ,Severity of Illness Index ,Article ,Nephropathy ,Diagnosis, Differential ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Focal segmental glomerulosclerosis ,Glomerulonephritis ,Sex Factors ,Membranous nephropathy ,Internal medicine ,medicine ,Humans ,Minimal change disease ,030212 general & internal medicine ,Prospective Studies ,Prospective cohort study ,Child ,Academic Medical Centers ,business.industry ,Glomerulosclerosis, Focal Segmental ,Nephrosis, Lipoid ,Biopsy, Needle ,Age Factors ,Glomerulonephritis, IGA ,Middle Aged ,medicine.disease ,Prognosis ,Immunohistochemistry ,Survival Analysis ,Nephrology ,Multivariate Analysis ,Disease Progression ,Linear Models ,Kidney Failure, Chronic ,Female ,business ,Kidney disease - Abstract
Rationale & Objectives Glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and immunoglobulin A (IgA) nephropathy, share clinical presentations, yet result from multiple biological mechanisms. Challenges to identifying underlying mechanisms, biomarkers, and new therapies include the rarity of each diagnosis and slow progression, often requiring decades to measure the effectiveness of interventions to prevent end-stage kidney disease (ESKD) or death. Study Design Multicenter prospective cohort study. Setting & Participants Cure Glomerulonephropathy (CureGN) will enroll 2,400 children and adults with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy (including IgA vasculitis) and a first diagnostic kidney biopsy within 5 years. Patients with ESKD and those with secondary causes of glomerular disease are excluded. Exposures Clinical data, including medical history, medications, family history, and patient-reported outcomes, are obtained, along with a digital archive of kidney biopsy images and blood and urine specimens at study visits aligned with clinical care 1 to 4 times per year. Outcomes Patients are followed up for changes in estimated glomerular filtration rate, disease activity, ESKD, and death and for nonrenal complications of disease and treatment, including infection, malignancy, cardiovascular, and thromboembolic events. Analytical Approach The study design supports multiple longitudinal analyses leveraging the diverse data domains of CureGN and its ancillary program. At 2,400 patients and an average of 2 years' initial follow-up, CureGN has 80% power to detect an HR of 1.4 to 1.9 for proteinuria remission and a mean difference of 2.1 to 3.0mL/min/1.73m2 in estimated glomerular filtration rate per year. Limitations Current follow-up can only detect large differences in ESKD and death outcomes. Conclusions Study infrastructure will support a broad range of scientific approaches to identify mechanistically distinct subgroups, identify accurate biomarkers of disease activity and progression, delineate disease-specific treatment targets, and inform future therapeutic trials. CureGN is expected to be among the largest prospective studies of children and adults with glomerular disease, with a broad goal to lessen disease burden and improve outcomes.
- Published
- 2018
218. Hydroxypropyl-β-cyclodextrin protects from kidney disease in experimental Alport syndrome and focal segmental glomerulosclerosis
- Author
-
Ion Volosenco, Alessia Fornoni, Alexis Sloan, Santiago Pastori, Sandra Merscher, Mengyuan Ge, Matthias Kretzler, Judith Molina, Armando J. Mendez, Jin Ju Kim, Patricia Wahl, Shamroop K. Mallela, Alla Mitrofanova, Jonathan Bryn, Ximena A. Morales, Sebastian Martini, Javier Varona Santos, G. Michelle Ducasa, Sean Eddy, Johanna Guzman, and George W. Burke
- Subjects
0301 basic medicine ,Collagen Type IV ,Pathology ,medicine.medical_specialty ,Biopsy ,Kidney Glomerulus ,Renal function ,Nephritis, Hereditary ,030204 cardiovascular system & hematology ,urologic and male genital diseases ,Autoantigens ,Article ,Nephropathy ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Focal segmental glomerulosclerosis ,medicine ,Animals ,Humans ,Alport syndrome ,Mice, Knockout ,Kidney ,business.industry ,urogenital system ,Glomerulosclerosis, Focal Segmental ,medicine.disease ,Lipid Metabolism ,female genital diseases and pregnancy complications ,2-Hydroxypropyl-beta-cyclodextrin ,Observational Studies as Topic ,030104 developmental biology ,medicine.anatomical_structure ,Cholesterol ,Nephrology ,Doxorubicin ,Tubulointerstitial fibrosis ,Albuminuria ,lipids (amino acids, peptides, and proteins) ,Female ,medicine.symptom ,business ,Kidney disease - Abstract
Studies suggest that altered renal lipid metabolism plays a role in the pathogenesis of diabetic kidney disease and that genetic or pharmacological induction of cholesterol efflux protects from the development of diabetic kidney disease and focal segmental glomerulosclerosis (FSGS). Here we tested whether altered lipid metabolism contributes to renal failure in the Col4a3 knockout mouse model for Alport Syndrome. There was an eight-fold increase in the cholesterol content in renal cortexes of mice with Alport Syndrome. This was associated with increased glomerular lipid droplets and cholesterol crystals. Treatment of mice with Alport Syndrome with hydroxypropyl-β-cyclodextrin (HPβCD) reduced cholesterol content in the kidneys of mice with Alport Syndrome and protected from the development of albuminuria, renal failure, inflammation and tubulointerstitial fibrosis. Cholesterol efflux and trafficking-related genes were primarily affected in mice with Alport Syndrome and were differentially regulated in the kidney cortex and isolated glomeruli. HPβCD also protected from proteinuria and mesangial expansion in a second model of non-metabolic kidney disease, adriamycin-induced nephropathy. Consistent with our experimental findings, microarray analysis confirmed dysregulation of several lipid-related genes in glomeruli isolated from kidney biopsies of patients with primary FSGS enrolled in the NEPTUNE study. Thus, lipid dysmetabolism occurs in non-metabolic glomerular disorders such as Alport Syndrome and FSGS, and HPβCD improves renal function in experimental Alport Syndrome and FSGS.
- Published
- 2018
219. Defining Glomerular Disease in Mechanistic Terms: Implementing an Integrative Biology Approach in Nephrology
- Author
-
William F. Pendergraft, Matthias Kretzler, and Laura H. Mariani
- Subjects
Epigenomics ,Proteomics ,0301 basic medicine ,Nephrology ,medicine.medical_specialty ,Genotype ,Epidemiology ,Kidney Glomerulus ,Population ,030232 urology & nephrology ,Datasets as Topic ,Signs and symptoms ,Disease ,Critical Care and Intensive Care Medicine ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Metabolomics ,Integrative biology ,Glomerular disease ,Liquid biopsy ,Intensive care medicine ,education ,Transplantation ,education.field_of_study ,business.industry ,Microbiota ,Computational Biology ,Precision medicine ,Glomerular Diseases: Update for the Clinician ,Phenotype ,030104 developmental biology ,Immunology ,Kidney Diseases ,Transcriptome ,business - Abstract
Advances in biomedical research allow for the capture of an unprecedented level of genetic, molecular, and clinical information from large patient cohorts, where the quest for precision medicine can be pursued. An overarching goal of precision medicine is to integrate the large–scale genetic and molecular data with deep phenotypic information to identify a new mechanistic disease classification. This classification can ideally be used to meet the clinical goal of the right medication for the right patient at the right time. Glomerular disease presents a formidable challenge for precision medicine. Patients present with similar signs and symptoms, which cross the current disease categories. The diseases are grouped by shared histopathologic features, but individual patients have dramatic variability in presentation, progression, and response to therapy, reflecting the underlying biologic heterogeneity within each glomerular disease category. Despite the clinical challenge, glomerular disease has several unique advantages to building multilayered datasets connecting genetic, molecular, and structural information needed to address the goals of precision medicine in this population. Kidney biopsy tissue, obtained during routine clinical care, provides a direct window into the molecular mechanisms active in the affected organ. In addition, urine is a biofluid ideally suited for repeated measurement from the diseased organ as a liquid biopsy with potential to reflect the dynamic state of renal tissue. In our review, current approaches for large–scale data generation and integration along the genotype-phenotype continuum in glomerular disease will be summarized. Several successful examples of this integrative biology approach within glomerular disease will be highlighted along with an outlook on how achieving a mechanistic disease classification could help to shape glomerular disease research and care in the future.
- Published
- 2016
220. Complete Remission in the Nephrotic Syndrome Study Network
- Author
-
Daniel C. Cattran, Alicia M. Neu, Patrick H. Nachman, Kevin V. Lemley, Matthew G. Sampson, Matthew Palmer, Laura H. Mariani, Michael J. Choi, Crystal A. Gadegbeku, Titilayo O. Ilori, Katherine R. Tuttle, Keisha L. Gibson, Sangeeta Hingorani, Frederick J. Kaskel, Christoph Licht, Cynthia C. Nast, Sharon G. Adler, Stephen M. Hewitt, Olga Zhdanova, Gerald B. Appel, Gaston Zilleruelo, J. Charles Jennette, Kevin E.C. Meyers, John R. Sedor, Jonathan P. Troost, Fernando C. Fervenza, Tammy M. Brady, Heather N. Reich, Jeffrey B. Kopp, Marie C. Hogan, Michelle Hladunewich, Duncan B. Johnstone, Kalyani Perumal, Susan L. Hogan, Marva Moxey-Mims, Richard A. Lafayette, Jeffrey B. Hodgin, Avi Z. Rosenberg, Howard Trachtman, Christine B. Sethna, Peter X.-K. Song, Peter J. Nelson, Michele H. Mokrzycki, Kamalanathan K. Sambandam, Serena M. Bagnasco, Debbie S. Gipson, John C. Lieske, Carmen Avila-Casado, Laura Barisoni-Thomas, Katherine MacRae Dell, Lawrence B. Holzman, Alessia Fornoni, Larry A. Greenbaum, and Matthias Kretzler
- Subjects
Adult ,Male ,medicine.medical_specialty ,Nephrotic Syndrome ,Adolescent ,Epidemiology ,Biopsy ,030232 urology & nephrology ,030204 cardiovascular system & hematology ,Kidney ,Critical Care and Intensive Care Medicine ,Gastroenterology ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Focal segmental glomerulosclerosis ,Membranous nephropathy ,Interquartile range ,Internal medicine ,Outcome Assessment, Health Care ,medicine ,Humans ,Minimal change disease ,Prospective Studies ,Proportional Hazards Models ,Transplantation ,Proteinuria ,medicine.diagnostic_test ,business.industry ,Remission Induction ,Hazard ratio ,Original Articles ,Middle Aged ,medicine.disease ,Surgery ,Nephrology ,Kidney Failure, Chronic ,Female ,Renal biopsy ,medicine.symptom ,business ,Nephrotic syndrome ,Glomerular Filtration Rate - Abstract
Background and objectives This analysis from the Nephrotic Syndrome Study Network (NEPTUNE) assessed the phenotypic and pathology characteristics of proteinuric patients undergoing kidney biopsy and defined the frequency and factors associated with complete proteinuria remission (CRever). Design, setting, participants, & measurements We enrolled adults and children with proteinuria ≥0.5 g/d at the time of first clinically indicated renal biopsy at 21 sites in North America from April 2010 to June 2014 into a prospective cohort study. NEPTUNE central pathologists assigned participants to minimal-change disease (MCD), FSGS, membranous nephropathy, or other glomerulopathy cohorts. Outcome measures for this analysis were (1) CRever with urine protein-to-creatinine ratio (UPC)
- Published
- 2016
221. Using Population Genetics to Interrogate the Monogenic Nephrotic Syndrome Diagnosis in a Case Cohort
- Author
-
Christopher E. Gillies, Virginia Vega-Warner, Brendan D. Crawford, Matthew G. Sampson, Hyun Min Kang, Matthias Kretzler, Catherine C. Robertson, and Edgar A. Otto
- Subjects
Adult ,0301 basic medicine ,Nephrotic Syndrome ,Adolescent ,Population ,Biology ,Bioinformatics ,Young Adult ,03 medical and health sciences ,Focal segmental glomerulosclerosis ,Genetic variation ,medicine ,Humans ,Expressivity (genetics) ,1000 Genomes Project ,Child ,education ,Aged ,Aged, 80 and over ,Genetics ,education.field_of_study ,General Medicine ,Middle Aged ,medicine.disease ,Penetrance ,Steroid-resistant nephrotic syndrome ,Basic Research ,Genetics, Population ,030104 developmental biology ,Nephrology ,Child, Preschool ,Cohort - Abstract
To maximize clinical benefits of genetic screening of patients with nephrotic syndrome (NS) to diagnose monogenic causes, reliably distinguishing NS-causing variants from the background of rare, noncausal variants prevalent in all genomes is vital. To determine the prevalence of monogenic NS in a North American case cohort while accounting for background prevalence of genetic variation, we sequenced 21 implicated monogenic NS genes in 312 participants from the Nephrotic Syndrome Study Network and 61 putative controls from the 1000 Genomes Project (1000G). These analyses were extended to available sequence data from approximately 2500 subjects from the 1000G. A typical pathogenicity filter identified causal variants for NS in 4.2% of patients and 5.8% of subjects from the 1000G. We devised a more stringent pathogenicity filtering strategy, reducing background prevalence of causal variants to 1.5%. When applying this stringent filter to patients, prevalence of monogenic NS was 2.9%; of these patients, 67% were pediatric, and 44% had FSGS on biopsy. The rate of complete remission did not associate with monogenic classification. Thus, we identified factors contributing to inaccurate monogenic classification of NS and developed a more accurate variant filtering strategy. The prevalence and clinical correlates of monogenic NS in this sporadically affected cohort differ substantially from those reported for patients referred for genetic analysis. Particularly in unselected, population-based cases, considering putative causal variants in known NS genes from a probabilistic rather than a deterministic perspective may be more precise. We also introduce GeneVetter, a web tool for monogenic assessment of rare disease.
- Published
- 2015
222. Angiotensin II up-regulates sodium-glucose co-transporter 2 expression and SGLT2 inhibitor attenuates Ang II-induced hypertensive renal injury in mice.
- Author
-
Miyata, Kana N., Chao-Sheng Lo, Shuiling Zhao, Min-Chun Liao, Yuchao Pang, Shiao-Ying Chang, Junzheng Peng, Matthias Kretzler, Filep, Janos G., Ingelfinger, Julie R., Shao-Ling Zhang, and Chan, John S. D.
- Subjects
ANGIOTENSIN II ,LOSARTAN ,SODIUM-glucose cotransporter 2 inhibitors ,RENIN-angiotensin system ,SYSTOLIC blood pressure ,ANGIOTENSIN converting enzyme ,HYPERTENSION - Abstract
Clinical trials indicate that sodium/glucose co-transporter 2 (SGLT2) inhibitors (SGLT2i) improve kidney function, yet, the molecular regulation of SGLT2 expression is incompletely understood. Here, we investigated the role of the intrarenal renin-angiotensin system (RAS) on SGLT2 expression. In adult non-diabetic participants in the Nephrotic Syndrome Study Network (NEPTUNE, n=163), multivariable linear regression analysis showed SGLT2 mRNA was significantly associated with angiotensinogen (AGT), renin, and angiotensin-converting enzyme (ACE) mRNA levels (P<0.001). In vitro, angiotensin II (Ang II) dose-dependently stimulated SGLT2 expression in HK-2, human immortalized renal proximal tubular cells (RPTCs); losartan and antioxidants inhibited it. Sglt2 expression was increased in transgenic (Tg) mice specifically overexpressing Agt in their RPTCs, as well as in WT mice with a single subcutaneous injection of Ang II (1.44mg/kg). Moreover, Ang II (1000 ng/kg/min) infusion via osmotic mini-pump in WT mice for 4 weeks increased systolic blood pressure (SBP), glomerulosclerosis, tubulointerstitial fibrosis, and albuminuria; canaglifozin (Cana, 15 mg/kg/day) reversed these changes, with the exception of SBP. Fractional glucose excretion (FeGlu) was higher in Ang II+Cana than WT+Cana, whereas Sglt2 expression was similar. Our data demonstrate a link between intrarenal RAS and SGLT2 expression and that SGLT2i ameliorates Ang II-induced renal injury independent of SBP. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
223. Network analysis of genes regulated in renal diseases: implications for a molecular-based classification.
- Author
-
Suresh K. Bhavnani, Felix Eichinger, Sebastian Martini, Paul Saxman, H. V. Jagadish, and Matthias Kretzler
- Published
- 2009
- Full Text
- View/download PDF
224. Prediction of transcriptional signatures in glomeruli of a mouse model of nephropathy using the human Global Prior rank
- Author
-
Matthias Kretzler, Laura Barisoni, Leslie A. Bruggeman, Agustin Gonzalez-Vicente, John R. Sedor, Zhenzhen Wu, John F. O’Toole, and Viji Nair
- Subjects
Genetics ,medicine ,Rank (graph theory) ,Computational biology ,Biology ,medicine.disease ,Molecular Biology ,Biochemistry ,Biotechnology ,Nephropathy - Published
- 2020
225. Redefining Nephrotic Syndrome in Molecular Terms: Outcome-associated molecular clusters and patient stratification with noninvasive surrogate biomarkers
- Author
-
Alessia Fornoni, Tarak Srivastava, Brad Godfrey, Viji Nair, Laura Barisoni, Cheryl L. Tran, Kevin E. Myers, Fernando C. Fervenza, Cindy C. Nast, Felix Eichinger, Howard Trachtman, Elizabeth J. Brown, Sharon G. Adler, Jeffrey B. Kopp, Gerry B. Appel, Vimal K. Derebail, John C. Lieske, Dan Cattran, John R. Sedor, Sangeeta Hingorani, John Hogan, Jen Jar Lin, Matthias Kretzler, Kamal Sambandam, J. Ashley Jefferson, Lawrence A. Greenbaum, Chia-shi Wang, Ambarish M. Athavale, Alicia M. Neu, Patrick H. Nachman, Lawrence B. Holzman, Sebastian Martini, Michelle A. Hlandunewich, Laura H. Mariani, Crystal A. Gadegbeku, Frederick J. Kaskel, Heather N. Reich, Kevin V. Lemley, Richard A. Lafayette, Keisha L. Gibson, Christine B. Sethna, Sean Eddy, Katherine MacRae Dell, and Deb Gipson
- Subjects
Oncology ,0303 health sciences ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,030232 urology & nephrology ,Disease ,medicine.disease ,Precision medicine ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Focal segmental glomerulosclerosis ,Internal medicine ,Biopsy ,Cohort ,medicine ,Minimal change disease ,business ,Nephrotic syndrome ,030304 developmental biology ,Kidney disease - Abstract
SummaryA tissue transcriptome driven classification of nephrotic syndrome patients identified a high risk group of patients with TNF activation and established a non-invasive marker panel for pathway activity assessment paving the way towards precision medicine trials in NS.AbstractNephrotic syndrome from primary glomerular diseases can lead to chronic kidney disease (CKD) and/or end-stage renal disease (ESRD). Conventional diagnoses using a combination of clinical presentation and descriptive biopsy information do not accurately predict risk for progression in patients with nephrotic syndrome, which complicates disease management. To address this challenge, a transcriptome-driven approach was used to classify patients with minimal change disease and focal segmental glomerulosclerosis in the Nephrotic Syndrome Study Network (NEPTUNE). Transcriptome-based classification revealed a group of patients at risk for disease progression. High risk patients had a transcriptome profile consistent with TNF activation. Non-invasive urine biomarkers TIMP1 and CCL2 (MCP1), which are causally downstream of TNF, accurately predicted TNF activation in the NEPTUNE cohort setting the stage for patient stratification approaches and precision medicine in kidney disease.
- Published
- 2018
- Full Text
- View/download PDF
226. Inflammatory and JAK-STAT Pathways as Shared Molecular Targets for ANCA-Associated Vasculitis and Nephrotic Syndrome
- Author
-
Laura H. Mariani, John Hartman, Matt G. Sampson, Matthias Kretzler, Huateng Huang, Brad Godfrey, Jaclyn N. Taroni, Sean Eddy, Richard A. Lafayette, Casey S. Greene, Felix E. Eichinger, Viji Nair, Peter C. Grayson, Wenjun Ju, Hemang Parikh, Peter A. Merkel, Maja T. Lindenmeyer, Clemens D. Cohen, and Jeffrey P. Krischer
- Subjects
0303 health sciences ,Kidney ,business.industry ,030232 urology & nephrology ,Renal function ,medicine.disease ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Focal segmental glomerulosclerosis ,medicine.anatomical_structure ,Membranous nephropathy ,Immunology ,Medicine ,Minimal change disease ,business ,Granulomatosis with polyangiitis ,Microscopic polyangiitis ,Nephrotic syndrome ,030304 developmental biology - Abstract
BackgroundGlomerular diseases of the kidney are presently differentiated, diagnosed and treated according to conventional clinical or structural features. While etiologically diverse, these diseases share common clinical features including but not limited to reduced glomerular filtration rate, increased serum creatinine and proteinuria suggesting shared pathogenic mechanisms across diseases. Renal biopsies from patients with nephrotic syndrome (NS) or ANCA-associated vasculitis (AAV) were evaluated for molecular signals cutting across conventional disease categories as candidates for therapeutic targets.MethodsRenal biopsies were obtained from patients with NS (minimal change disease, focal segmental glomerulosclerosis, or membranous nephropathy) (n=187) or AAV (granulomatosis with polyangiitis or microscopic polyangiitis) (n=80) from the Nephrotic Syndrome Study Network (NEPTUNE) and the European Renal cDNA Bank. Transcriptional profiles were assessed for shared disease mechanisms.ResultsIn the discovery cohort, 10–25% transcripts were differentially regulated versus healthy controls in both NS and AAV, >500 transcripts were shared across diseases. The majority of shared transcripts (60–77%) were validated in independent samples. Therapeutically targetable networks were identified, including inflammatory JAK-STAT signaling. STAT1 eQTLs were identified and STAT1 expression associated with GFR-based outcome. A transcriptional STAT1 activity score was generated from STAT1-regulated target genes which correlated with CXCL10 (pConclusionAAV and NS caused from histopathologically distinct disease categories share common intra-renal molecular pathways cutting across conventional disease classifications. This approach provides a starting point for de novo drug development, and repurposing efforts in rare kidney diseases.
- Published
- 2018
227. Organoid single cell profiling identifies a transcriptional signature of glomerular disease
- Author
-
Noel L. Wys, Matthias Kretzler, Roger C. Wiggins, Sean Eddy, Jinghui Luo, Christopher L. O’Connor, Markus Bitzer, Edgar A. Otto, Jennifer L. Harder, Benjamin S. Freedman, Viji Nair, Rajasree Menon, Jeffrey B. Hodgin, Olga G. Troyanskaya, Jian Zhou, Jason R. Spence, and Cristina Cebrian
- Subjects
0301 basic medicine ,Nephrology ,Adult ,Pluripotent Stem Cells ,medicine.medical_specialty ,Kidney Glomerulus ,Biology ,Podocyte ,Tissue Culture Techniques ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Organoid ,Humans ,Induced pluripotent stem cell ,Embryonic Stem Cells ,Kidney ,urogenital system ,Podocytes ,General Medicine ,medicine.disease ,Embryonic stem cell ,Cell biology ,Gene expression profiling ,Organoids ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Kidney Diseases ,Single-Cell Analysis ,Transcriptome ,Kidney disease ,Research Article - Abstract
Podocyte injury is central to many forms of kidney disease, but transcriptional signatures reflecting podocyte injury and compensation mechanisms are challenging to analyze in vivo. Human kidney organoids derived from pluripotent stem cells (PSCs), a potentially new model for disease and regeneration, present an opportunity to explore the transcriptional plasticity of podocytes. Here, transcriptional profiling of more than 12,000 single cells from human PSC-derived kidney organoid cultures was used to identify robust and reproducible cell lineage gene expression signatures shared with developing human kidneys based on trajectory analysis. Surprisingly, the gene expression signature characteristic of developing glomerular epithelial cells was also observed in glomerular tissue from a kidney disease cohort. This signature correlated with proteinuria and inverse eGFR, and it was confirmed in an independent podocytopathy cohort. Three genes in particular were further characterized as potentially novel components of the glomerular disease signature. We conclude that cells in human PSC-derived kidney organoids reliably recapitulate the developmental transcriptional program of podocytes and other cell lineages in the human kidney and that transcriptional profiles seen in developing podocytes are reactivated in glomerular disease. Our findings demonstrate an approach to identifying potentially novel molecular programs involved in the pathogenesis of glomerulopathies.
- Published
- 2018
228. MultiPLIER: a transfer learning framework for transcriptomics reveals systemic features of rare disease
- Author
-
Peter C. Grayson, Qiwen Hu, Casey S. Greene, Matthias Kretzler, Peter A. Merkel, Jaclyn N. Taroni, and Sean Eddy
- Subjects
Histology ,Computer science ,Genomics ,Machine learning ,computer.software_genre ,Article ,Pathology and Forensic Medicine ,Extractor ,Transcriptome ,Machine Learning ,03 medical and health sciences ,0302 clinical medicine ,Rare Diseases ,Disease severity ,Gene expression ,Humans ,030304 developmental biology ,0303 health sciences ,business.industry ,Gene Expression Profiling ,Computational Biology ,Cell Biology ,Compendium ,Expression (mathematics) ,Term (time) ,ComputingMethodologies_PATTERNRECOGNITION ,Unsupervised learning ,Multiplier (economics) ,Artificial intelligence ,Transfer of learning ,business ,computer ,030217 neurology & neurosurgery ,Rare disease ,Unsupervised Machine Learning - Abstract
SUMMARYUnsupervised machine learning methods provide a promising means to analyze and interpret large datasets. However, most gene expression datasets generated by individual researchers remain too small to fully benefit from these methods. In the case of rare diseases, there may be too few cases available, even when multiple studies are combined. We trained a Pathway Level Information ExtractoR (PLIER) model using on a large public data compendium comprised of multiple experiments, tissues, and biological conditions. We then transferred the model to small rare disease datasets in an approach we term MultiPLIER. Models constructed from large, diverse public data i) included features that aligned well to important biological factors; ii) were more comprehensive than those constructed from individual datasets or conditions; iii) transferred to rare disease datasets where the models describe biological processes related to disease severity more effectively than models trained on specifically those datasets.
- Published
- 2018
- Full Text
- View/download PDF
229. Thrombin Generation in Nephrotic Syndrome Is Dependent on Remission Status and Hypercholestrolemia
- Author
-
Bryce A. Kerlin, Jonathan P. Troost, Samir M. Parikh, Amanda P. Waller, Matthias Kretzler, and William E. Smoyer
- Subjects
Creatinine ,medicine.medical_specialty ,Proteinuria ,biology ,medicine.diagnostic_test ,Cholesterol ,business.industry ,Immunology ,Serum albumin ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Gastroenterology ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Hyperlipidemia ,Severity of illness ,medicine ,biology.protein ,medicine.symptom ,business ,Lipid profile ,Nephrotic syndrome - Abstract
Nephrotic syndrome (NS) is associated with a complex acquired hypercoagulopathy and a strong predilection for venous thromboembolic (VTE) complications. Thromboembolic disease complicates an estimated 27% of adult and 3% of pediatric NS cases. Nonetheless, routine prophylactic anticoagulation for NS remains controversial due to a lack of randomized trials demonstrating safety (bleeding) and efficacy as well as a lack to validated VTE-risk markers. We and others have previously shown that NS disease severity, as determined by proteinuria and serum albumin, is correlated with VTE-risk and may thus be a useful guide to thromboprophylaxis in the future. In animal models we have shown that hypercoagulopathy, as determined by thrombin generation assay (TGA), is proportional to NS severity and others have shown that TGA has predictive value for both incident and recurrent VTE in non-NS patients. We thus sought to determine the relationship between TGA and NS severity in human disease. Standard sodium citrate plasma aliquots (N=150) were obtained from the Nephrotic Syndrome Study Network (NEPTUNE) biorepository. Patients taking anticoagulants or antiplatelet agents were excluded. Correlated phenotypic data for each sample was collected from the NEPTUNE database. The NEPTUNE protocol defined complete NS remission a priori as UP:C TGA was undetectable in 3 (2%) of the NEPTUNE samples and those samples were excluded from further analysis. Univariate linear regression of ETP on the remaining 147 samples revealed significant relationships with age (B -16), proteinuria (log-urinary protein:creatinine ratio (UP:C); B 490), plasma albumin (B -657), and lipid profile components (e.g. total cholesterol B 2,129). Histologic classification of NS was not associated with ETP. ETP was significantly higher during active disease (no remission) than during complete or partial remission (Figure A). Non-linear regression modeling revealed a polynomial relationship between UP:C and ETP (Figure B) with a nadir ETP at UP:C 0.28. Multivariable modeling revealed that log-Total Cholesterol, log-UP:C (polynomial), Plasma Albumin, and Age were independently predictive of ETP (P values Proteinuria, plasma albumin, and hyperlipidemia are strongly associated with hypercoagulopathy as assessed by ETP during active NS. Analyzing these NS severity markers and ETP in relation to thrombotic events in future studies may inform their utility to guide the clinical application of thromboprophylaxis for NS patients. Disclosures Kerlin: Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Research Funding.
- Published
- 2019
230. The immune cell landscape in kidneys of lupus nephritis patients
- Author
-
David A. Hildeman, Meyeon Park, Yanyan Liu, Deepak A. Rao, Edward P. Browne, Elena Massarotti, Jill P. Buyon, Shuqiang Li, A. Helena Jonsson, Nir Hacohen, David Wofsy, Michael B. Brenner, William Apruzzese, Patti Tosta, Chad Nusbaum, Fernanda Payan-Schober, Anne Davidson, Jennifer H. Anolik, Paul Hoover, David J. Lieb, Chaim Putterman, Betty Diamond, Akiko Noma, Maria Dall'Era, Richard A. Furie, Scott Steelman, James A. Lederer, Diane L. Kamen, E. Steve Woodle, Kenneth C. Kalunian, Michelle Petri, Thomas Eisenhaure, Celine C. Berthier, Dawn E. Smilek, Danielle Sutherby, Arnon Arazi, Adam Chicoine, and Matthias Kretzler
- Subjects
Autoimmune disease ,0303 health sciences ,Kidney ,Myeloid ,business.industry ,Lupus nephritis ,medicine.disease ,3. Good health ,03 medical and health sciences ,Chemokine receptor ,0302 clinical medicine ,medicine.anatomical_structure ,Immune system ,Monocyte differentiation ,Immunology ,Medicine ,business ,B cell ,030304 developmental biology ,030215 immunology - Abstract
Lupus nephritis is a potentially fatal autoimmune disease, whose current treatment is ineffective and often toxic. To gain insights into disease mechanisms, we analyzed kidney samples from lupus nephritis patients and healthy controls using single-cell RNA-seq. Our analysis revealed 21 subsets of leukocytes active in disease, including multiple populations of myeloid, T, NK and B cells, demonstrating both pro-inflammatory and resolving responses. We found evidence of local activation of B cells correlated with an age-associated B cell signature, and of progressive stages of monocyte differentiation within the kidney. A clear interferon response was observed in most cells. Two chemokine receptors, CXCR4 and CX3CR1, were broadly expressed, pointing to potential therapeutic targets. Gene expression of immune cells in urine and kidney was highly correlated, suggesting urine may be a surrogate for kidney biopsies. Our results provide a first comprehensive view of the complex network of leukocytes active in lupus nephritis kidneys.
- Published
- 2018
- Full Text
- View/download PDF
231. Renal matrix Gla protein expression increases progressively with CKD and predicts renal outcome
- Author
-
Leon J. Schurgers, Sharon G. Adler, Janine LaPage, Jonathan P. Troost, Kana N. Miyata, Ramanath Dukkipati, Cynthia C. Nast, Matthias Kretzler, Tiane Dai, Biochemie, and RS: CARIM - R1.02 - Vascular aspects thrombosis and haemostasis
- Subjects
CHRONIC KIDNEY-DISEASE ,Vitamin K ,medicine.medical_treatment ,Clinical Biochemistry ,030232 urology & nephrology ,030204 cardiovascular system & hematology ,urologic and male genital diseases ,Kidney ,NEPTUNE ,DISEASE ,Rats, Sprague-Dawley ,Ectopic calcification ,0302 clinical medicine ,Chronic kidney disease ,NEPHROTIC SYNDROME ,Matrix gla protein ,PHOSPHATE ,NETWORK ,Bone morphogenesis ,Extracellular Matrix Proteins ,biology ,Nephrectomy ,medicine.anatomical_structure ,medicine.medical_specialty ,NEPHROPATHY ,Renal function ,Article ,Pathology and Forensic Medicine ,Nephropathy ,03 medical and health sciences ,Internal medicine ,medicine ,Animals ,Humans ,Renal outcome ,Renal Insufficiency, Chronic ,Molecular Biology ,business.industry ,Calcium-Binding Proteins ,nutritional and metabolic diseases ,medicine.disease ,CALCIFICATION ,Rats ,Endocrinology ,biology.protein ,Gene expression ,business ,Nephrotic syndrome ,Biomarkers ,K-DEPENDENT PROTECTION - Abstract
Background: Matrix Gla Protein (MGP) is a potent inhibitor of ectopic calcification and modulates bone morphogenesis. Little is known about MGP expression or function in kidney. Methods: We investigated renal MGP expression in Sprague-Dawley rats after 5/6 nephrectomy (5/6 Nx) and in human kidney biopsies in the Nephrotic Syndrome Study Network (NEPTUNE) cohort. We analyzed associations between glomerular (n = 182) and tubulointerstitial (TI) (n = 219) MGP mRNA levels and the disease activity/histologic features in NEPTUNE patients. Additionally, uncarboxylated and carboxylated MGP (ucMGP and cMGP, respectively) were localized by immunohistochemistry and quantitated in kidney tissues of patients at different stages of CKD (n = 18). Results: Renal MGP expression was increased in rats after 5/6 Nx. In NEPTUNE data, baseline estimated glomerular filtration rate (eGFR) negatively correlated with glomerular and TI MGP expression (p < 0.001). TI MGP expression strongly correlated with interstitial fibrosis, tubular atrophy, acute tubular injury, and interstitial inflammation, independent of eGFR. Kaplan-Meier analysis and multivariable Cox regression showed that higher levels of TI MGP expression were associated with an increased risk for the composite of 40% decline in eGFR and end-stage renal disease (ESRD) (HR, 3.31; 95% CI, 1.31 to 6.32; p = 0.02). Glomerular and tubulointerstitial cells demonstrated nuclear and cytoplasmic cMGP and ucMGP staining, and eGFR inversely correlated with quantified glomerular cMGP staining (p < 0.05). Conclusions: Our data demonstrate that renal MGP expression is increased in human and experimental CKD, and is associated with renal outcome. Additional studies are needed to determine its mechanism of action.
- Published
- 2018
232. Validation of plasma biomarker candidates for the prediction of eGFR decline in patients with type 2 diabetes
- Author
-
Susanne Eder, Georg Heinze, Karin Hu, Peter S. Gilmour, Patrick B. Mark, Roman Reindl-Schwaighofer, László Rosivall, Andreas Heinzel, Matthias Kretzler, Hiddo J.L. Heerspink, Gert Mayer, Moustafa Abdalla, Andrzej Wiecek, Paul Perco, Maria F. Gomez, Kevin L. Duffin, Jonathan M. Wilson, Mark I. McCarthy, Michael Kammer, Wenjun Ju, Rainer Oberbauer, Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Groningen Kidney Center (GKC), and Methods in Medicines evaluation & Outcomes research (M2O)
- Subjects
Male ,Oncology ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,030232 urology & nephrology ,Renal function ,PROGRESSION ,Type 2 diabetes ,030204 cardiovascular system & hematology ,Kidney Function Tests ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Diabetes mellitus ,Internal medicine ,Internal Medicine ,medicine ,CKD ,Humans ,Diabetic Nephropathies ,COHORT ,Longitudinal Studies ,ESRD ,Pathophysiology/Complications ,Prospective cohort study ,Aged ,Advanced and Specialized Nursing ,CLINICAL-PRACTICE GUIDELINE ,business.industry ,Type 2 Diabetes Mellitus ,KIDNEY-DISEASE ,ASSOCIATION ,Middle Aged ,medicine.disease ,TNFR1 ,Diabetes Mellitus, Type 2 ,Cohort ,Biomarker (medicine) ,UPDATE ,Female ,business ,RENAL-FUNCTION DECLINE ,Biomarkers ,Glomerular Filtration Rate ,Cohort study - Abstract
OBJECTIVE The decline of estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes is variable, and early interventions would likely be cost-effective. We elucidated the contribution of 17 plasma biomarkers to the prediction of eGFR loss on top of clinical risk factors. RESEARCH DESIGN AND METHODS We studied participants in PROVALID (PROspective cohort study in patients with type 2 diabetes mellitus for VALIDation of biomarkers), a prospective multinational cohort study of patients with type 2 diabetes and a follow-up of more than 24 months (n = 2,560; baseline median eGFR, 84 mL/min/1.73 m2; urine albumin-to-creatinine ratio, 8.1 mg/g). The 17 biomarkers were measured at baseline in 481 samples using Luminex and ELISA. The prediction of eGFR decline was evaluated by linear mixed modeling. RESULTS In univariable analyses, 9 of the 17 markers showed significant differences in median concentration between stable and fast-progressing patients. A linear mixed model for eGFR obtained by variable selection exhibited an adjusted R2 of 62%. A panel of 12 biomarkers was selected by the procedure and accounted for 34% of the total explained variability, of which 32% was due to 5 markers. The individual contribution of each biomarker to the prediction of eGFR decline on top of clinical predictors was generally low. When included into the model, baseline eGFR exhibited the largest explained variability of eGFR decline (R2 of 79%), and the contribution of each biomarker dropped below 1%. CONCLUSIONS In this longitudinal study of patients with type 2 diabetes and maintained eGFR at baseline, 12 of the 17 candidate biomarkers were associated with eGFR decline, but their predictive power was low.
- Published
- 2018
233. Renin-Angiotensin System Inhibition Alters Triacylglycerol Metabolism in Diabetic Kidney Disease
- Author
-
Viji Nair, Kelli M. Sas, Subramaniam Pennathur, Matthias Kretzler, Jiahe Lin, and Frank C. Brosius
- Subjects
medicine.medical_specialty ,Creatinine ,Kidney ,biology ,business.industry ,Cholesterol ,Endocrinology, Diabetes and Metabolism ,Lisinopril ,biology.organism_classification ,medicine.disease ,chemistry.chemical_compound ,Losartan ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Enos ,Internal medicine ,Diabetes mellitus ,Renin–angiotensin system ,Internal Medicine ,Medicine ,business ,medicine.drug - Abstract
Lipids are essential metabolites with diverse functions impacting physiology. We recently identified several lipidomic abnormalities in diabetic kidney disease (DKD), including remodeling of triacylglycerol (TAG) fatty acid composition to increase availability of long, polyunsaturated TAGs. Using the BKS eNOS-/- db/db diabetic mouse model, we studied the effect of renin-angiotensin system (RAS) inhibition with combination treatment of lisinopril (20 mg/kg/d) and losartan (30 mg/kg/d) for 12 weeks, an intervention which ameliorates DKD in this mouse model without impacting glycemia. We examined the kidney cortical lipidome to identify lipid alterations that may be pathogenic in DKD. As expected, RAS inhibition did not significantly alter glycemic control or total plasma triglycerides or cholesterol, but decreased the 24-hour urine albumin/creatinine ratio (2564 vs. 615 μg/mg creatinine) and decreased the glomerular periodic acid-Schiff stained area by 13% (p Disclosure K. Sas: None. J. Lin: None. V. Nair: None. M. Kretzler: Research Support; Self; AstraZeneca, Novo Nordisk Inc., Boehringer Ingelheim GmbH, National Institute of Diabetes and Digestive and Kidney Diseases, Eli Lilly and Company, Gilead Sciences, Inc.. F. Brosius: None. S. Pennathur: None.
- Published
- 2018
234. Proteomic Profile of Circulating Inflammatory Proteins Associated with 10-Year Risk of ESRD in T1 and T2 Diabetes—Enrichment for TNF Receptor Superfamily Members
- Author
-
John Tsay, Jan K. Skupien, Katalin Susztak, Andrzej Krolewski, Wenjun Ju, Christopher A. Simeone, Adam Smiles, Monika Niewczas, Jihwan Park, Matthias Kretzler, V. Nair, and Eiichiro Satake
- Subjects
Oncology ,Type 1 diabetes ,medicine.medical_specialty ,Proteomic Profile ,business.industry ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,IL18R1 ,medicine.disease ,Cytokine ,Diabetes mellitus ,Internal medicine ,Cohort ,Internal Medicine ,medicine ,Receptor ,business ,Cohort study - Abstract
We conducted an untargeted proteomic profiling of circulating inflammatory proteins using SOMASCAN platform to find those that predicted 10-year ESRD risk in two cohort study. Subjects with Type 1 Diabetes (T1D) served as a discovery cohort and a T2D cohort was used in validation. We identified a kidney risk inflammatory signature (KRIS) that robustly predicted progression to ESRD. The signature comprised 17 proteins out of 194 examined. KRIS was enriched for members of TNFR Superfamily (p=0.007) including TNFR1, TNFR2, TNFRSF19, TNFRSF19L, TNFRSF21 and TNFRSF27. Other KRIS proteins included IL15RA, IL17F, DAF, CLM6, TNFSF15, CCL14, CCL15, CSF1, TIMD3, IL1R1 and IL18R1. Hazard ratio (95% CI) for the top KRIS protein, TNFR1 was 3.6 (2.8, 4.6), p < 10-25. KRIS was neither enriched in receptors for other cytokines nor in cytokine ligands. Pathway analyses pointed to candidate therapeutic targets and aligned them by ranks. Eight proteins are currently targeted with compounds used for other clinical indications. Kidney tissue expression analysis and urinary proteomics suggested a systemic source of KRIS proteins. In summary, our study identifies and validates a powerful protein signature enriched in TNFRSF members associated with 10-year ESRD risk in diabetes. These findings should inform future drug development strategies. Disclosure M. Niewczas: None. J.K. Skupien: None. V. Nair: None. A. Smiles: None. J. Park: None. E. Satake: None. C.A. Simeone: None. J. Tsay: None. W. Ju: None. M. Kretzler: Research Support; Self; AstraZeneca, Novo Nordisk Inc., Boehringer Ingelheim GmbH, National Institute of Diabetes and Digestive and Kidney Diseases, Eli Lilly and Company, Gilead Sciences, Inc. K. Susztak: Research Support; Self; Regeneron Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., GlaxoSmithKline plc., Merck & Co., Inc., Eli Lilly and Company, Ono Pharmaceutical Co., Ltd.. A. Krolewski: None.
- Published
- 2018
235. LRG1 Promotes Diabetic Kidney Disease Progression by Enhancing TGF
- Author
-
Quan, Hong, Lu, Zhang, Jia, Fu, Divya A, Verghese, Kinsuk, Chauhan, Girish N, Nadkarni, Zhengzhe, Li, Wenjun, Ju, Matthias, Kretzler, Guang-Yan, Cai, Xiang-Mei, Chen, Vivette D, D'Agati, Steven G, Coca, Detlef, Schlondorff, John C, He, and Kyung, Lee
- Subjects
Male ,Neovascularization, Pathologic ,Podocytes ,Activin Receptors, Type II ,Kidney Glomerulus ,Endothelial Cells ,Smad Proteins ,Middle Aged ,Diabetes Mellitus, Experimental ,Basic Research ,Diabetes Mellitus, Type 2 ,Transforming Growth Factor beta ,Gene Knockdown Techniques ,Disease Progression ,Animals ,Humans ,Kidney Failure, Chronic ,Diabetic Nephropathies ,Female ,RNA, Messenger ,Glomerular Filtration Rate ,Glycoproteins ,Signal Transduction - Abstract
BACKGROUND: Glomerular endothelial dysfunction and neoangiogenesis have long been implicated in the pathogenesis of diabetic kidney disease (DKD). However, the specific molecular pathways contributing to these processes in the early stages of DKD are not well understood. Our recent transcriptomic profiling of glomerular endothelial cells identified a number of proangiogenic genes that were upregulated in diabetic mice, including leucine-rich α-2-glycoprotein 1 (LRG1). LRG1 was previously shown to promote neovascularization in mouse models of ocular disease by potentiating endothelial TGF-β/activin receptor-like kinase 1 (ALK1) signaling. However, LRG1’s role in the kidney, particularly in the setting of DKD, has been unclear. METHODS: We analyzed expression of LRG1 mRNA in glomeruli of diabetic kidneys and assessed its localization by RNA in situ hybridization. We examined the effects of genetic ablation of Lrg1 on DKD progression in unilaterally nephrectomized, streptozotocin-induced diabetic mice at 12 and 20 weeks after diabetes induction. We also assessed whether plasma LRG1 was associated with renal outcome in patients with type 2 diabetes. RESULTS: LRG1 localized predominantly to glomerular endothelial cells, and its expression was elevated in the diabetic kidneys. LRG1 ablation markedly attenuated diabetes-induced glomerular angiogenesis, podocyte loss, and the development of diabetic glomerulopathy. These improvements were associated with reduced ALK1-Smad1/5/8 activation in glomeruli of diabetic mice. Moreover, increased plasma LRG1 was associated with worse renal outcome in patients with type 2 diabetes. CONCLUSIONS: These findings identify LRG1 as a potential novel pathogenic mediator of diabetic glomerular neoangiogenesis and a risk factor in DKD progression.
- Published
- 2018
236. Clinical Characteristics and Treatment Patterns of Children and Adults With IgA Nephropathy or IgA Vasculitis: Findings From the CureGN Study
- Author
-
David T. Selewski, Josephine M. Ambruzs, Gerald B. Appel, Andrew S. Bomback, Raed Bou Matar, Yi Cai, Daniel C. Cattran, Aftab S. Chishti, Vivette D. D'Agati, Cynthia J. D'Alessandri-Silva, Rasheed A. Gbadegesin, Jonathan J. Hogan, Sandra Iragorri, J. Charles Jennette, Bruce A. Julian, Myda Khalid, Richard A. Lafayette, Helen Liapis, Francesca Lugani, Sarah A. Mansfield, Sherene Mason, Patrick H. Nachman, Cynthia C. Nast, Carla M. Nester, Damien G. Noone, Jan Novak, Michelle M. O'Shaughnessy, Heather N. Reich, Michelle N. Rheault, Dana V. Rizk, Manish K. Saha, Neil S. Sanghani, C. John Sperati, Rajasree Sreedharan, Tarak Srivastava, Agnieszka Swiatecka-Urban, Katherine Twombley, Tetyana L. Vasylyeva, Donald J. Weaver, Hong Yin, Jarcy Zee, Ronald J. Falk, Ali G. Gharavi, Brenda W. Gillespie, Debbie S. Gipson, Larry A. Greenbaum, Lawrence B. Holzman, Matthias Kretzler, Bruce M. Robinson, William E. Smoyer, Michael Flessner, Lisa M. Guay-Woodford, Krzysztof Kiryluk, Ali Gharavi, Wooin Ahn, Rupali S. Avasare, Revekka Babayev, Ibrahim Batal, Eric Brown, Eric S. Campenot, Pietro Canetta, Brenda Chan, Vivette D. D’Agati, Hilda Fernandez, Bartosz Foroncewicz, Gian Marco Ghiggeri, William H. Hines, Namrata G. Jain, Fangming Lin, Maddalena Marasa, Glen Markowitz, Sumit Mohan, Krzysztof Mucha, Thomas L. Nickolas, Jai Radhakrishnan, Maya K. Rao, Renu Regunathan-Shenk, Simone Sanna-Cherchi, Dominick Santoriello, Michael B. Stokes, Natalie Yu, Anthony M. Valeri, Ronald Zviti, Amira Al-Uzri, Isa Ashoor, Diego Aviles, Rossana Baracco, John Barcia, Sharon Bartosh, Craig Belsha, Michael C. Braun, Aftab Chishti, Donna Claes, Carl Cramer, Keefe Davis, Elif Erkan, Daniel Feig, Michael Freundlich, Melisha Hanna, Guillermo Hidalgo, Amrish Jain, Mahmoud Kallash, Jerome C. Lane, John Mahan, Nisha Mathews, Carla Nester, Cynthia Pan, Hiren Patel, Adelaide Revell, Julia Steinke, Scott E. Wenderfer, Craig S. Wong, Ronald Falk, William Cook, Vimal Derebail, Agnes Fogo, Adil Gasim, Todd Gehr, Raymond Harris, Jason Kidd, Louis-Philippe Laurin, Will Pendergraft, Vincent Pichette, Thomas Brian Powell, Matthew B. Renfrow, Virginie Royal, Sharon Adler, Charles Alpers, Elizabeth Brown, Daniel Cattran, Michael Choi, Katherine M. Dell, Ram Dukkipati, Fernando C. Fervenza, Alessia Fornoni, Crystal Gadegbeku, Patrick Gipson, Leah Hasely, Sangeeta Hingorani, Michelle A. Hladunewich, Jonathan Hogan, J. Ashley Jefferson, Kenar Jhaveri, Duncan B. Johnstone, Frederick Kaskel, Amy Kogan, Jeffrey Kopp, Kevin V. Lemley, Laura Malaga- Dieguez, Kevin Meyers, Alicia Neu, Michelle Marie O’Shaughnessy, John F. O’Toole, Rulan Parekh, Heather Reich, Kimberly Reidy, Helbert Rondon, Kamalanathan K. Sambandam, John R. Sedor, Christine B. Sethna, Jeffrey Schelling, Agnes Swiatecka-Urban, Howard Trachtman, Katherine R. Tuttle, Joseph Weisstuch, Olga Zhdanova, Brenda Gillespie, Laura Barisoni, Sarah Mansfield, Laura Mariani, and Matthew Wladkowski
- Subjects
medicine.medical_specialty ,030232 urology & nephrology ,Disease ,030204 cardiovascular system & hematology ,urologic and male genital diseases ,Nephropathy ,03 medical and health sciences ,0302 clinical medicine ,Focal segmental glomerulosclerosis ,Membranous nephropathy ,Clinical Research ,Internal medicine ,IgA nephropathy (IgAN) ,Biopsy ,medicine ,Minimal change disease ,medicine.diagnostic_test ,business.industry ,IgA vasculitis (IgAV) ,medicine.disease ,3. Good health ,IgA vasculitis ,Nephrology ,Cohort ,business ,glomerulonephritis ,Henoch-Schönlein purpura (HSP) - Abstract
Introduction The Cure Glomerulonephropathy Network (CureGN) is a 66-center longitudinal observational study of patients with biopsy-confirmed minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy (IgAN), including IgA vasculitis (IgAV). This study describes the clinical characteristics and treatment patterns in the IgA cohort, including comparisons between IgAN versus IgAV and adult versus pediatric patients. Methods Patients with a diagnostic kidney biopsy within 5 years of screening were eligible to join CureGN. This is a descriptive analysis of clinical and treatment data collected at the time of enrollment. Results A total of 667 patients (506 IgAN, 161 IgAV) constitute the IgAN/IgAV cohort (382 adults, 285 children). At biopsy, those with IgAV were younger (13.0 years vs. 29.6 years, P < 0.001), more frequently white (89.7% vs. 78.9%, P = 0.003), had a higher estimated glomerular filtration rate (103.5 vs. 70.6 ml/min per 1.73 m2, P < 0.001), and lower serum albumin (3.4 vs. 3.8 g/dl, P < 0.001) than those with IgAN. Adult and pediatric individuals with IgAV were more likely than those with IgAN to have been treated with immunosuppressive therapy at or prior to enrollment (79.5% vs. 54.0%, P < 0.001). Conclusion This report highlights clinical differences between IgAV and IgAN and between children and adults with these diagnoses. We identified differences in treatment with immunosuppressive therapies by disease type. This description of baseline characteristics will serve as a foundation for future CureGN studies.
- Published
- 2018
237. Health-related quality of life in glomerular disease
- Author
-
Pietro A. Canetta, Jonathan P. Troost, Shannon Mahoney, Amy J. Kogon, Noelle Carlozzi, Sharon M. Bartosh, Yi Cai, T. Keefe Davis, Hilda Fernandez, Alessia Fornoni, Rasheed A. Gbadegesin, Emily Herreshoff, John D. Mahan, Patrick H. Nachman, David T. Selewski, Christine B. Sethna, Tarak Srivastava, Katherine R. Tuttle, Chia-shi Wang, Ronald J. Falk, Ali G. Gharavi, Brenda W. Gillespie, Larry A. Greenbaum, Lawrence B. Holzman, Matthias Kretzler, Bruce M. Robinson, William E. Smoyer, Lisa M. Guay-Woodford, Bryce Reeve, Debbie S. Gipson, Wooin Ahn, Gerald B. Appel, Revekka Babayev, Ibrahim Batal, Andrew S. Bomback, Eric Brown, Eric S. Campenot, Pietro Canetta, Lucrezia Carlassara, Brenda Chan, Debanjana Chatterjee, Vivette D. D’Agati, Elisa Delbarba, Samriti Dogra, Bartosz Foroncewicz, Gian Marco Ghiggeri, William H. Hines, S. Ali Husain, Namrata G. Jain, Pascale Khairallah, Byum Hee Kil, Krzysztof Kiryluk, Anushya Jeyabalan, Wai L. Lau, Fangming Lin, Francesca Lugani, Maddalena Marasa, Glen Markowitz, Sumit Mohan, Xueru Mu, Krzysztof Mucha, Thomas L. Nickolas, Stacy Piva, Jai Radhakrishnan, Maya K. Rao, Regunathan-Shenk Renu, Simone Sanna-Cherchi, Dominick Santoriello, Shayan Shirazian, Michael B. Stokes, Natalie Uy, Anthony M. Valeri, Amira Al-Uzri, Josephine Ambruzs, Isa Ashoor, Diego Aviles, Rossana Baracco, John Barcia, Sharon Bartosh, Craig Belsha, Corinna Bowers, Michael C. Braun, Vladimir Chernitskiy, Aftab Chishti, Donna Claes, Kira Clark, Carl Cramer, Keefe Davis, Elif Erkan, Daniel Feig, Michael Freundlich, Joseph Gaut, Rasheed Gbadegesin, Melisha Hanna, Guillermo Hidalgo, David Hooper, Tracy E. Hunley, Amrish Jain, Mahmoud Kallash, Margo Kamel, Myda Khalid, Jon B. Klein, Theresa Kump, Jerome C. Lane, Helen Liapis, John Mahan, Carla Nester, Cynthia Pan, Larry Patterson, Hiren Patel, Alice Raad, Adelaide Revell, Michelle N. Rheault, Cynthia Silva, Rajasree Sreedharan, Julia Steinke, Susan Sumner, Katherine Twombley, Scott E. Wenderfer, Tetyana L. Vasylyeva, Donald J. Weaver, Craig S. Wong, Hong Yin, Anand Achanti, Salem Almaani, Isabelle Ayoub, Milos Budisavljevic, Maggie D’Angelo, Huma Fatima, Ronald Falk, Agnes Fogo, Keisha Gibson, Dorey Glenn, Susan Hogan, J. Charles Jennette, Bruce Julian, Jason Kidd, Louis-Philippe Laurin, H. Davis Massey, Amy Mottl, Shannon Murphy, Patrick Nachman, Tibor Nadasdy, Jan Novak, Samir Parikh, Caroline Poulton, Thomas Brian Powell, Matthew Renfrow, Monica Reynolds, Dana Rizk, Brad Rovin, Virginie Royal, Neil Sanghani, Sally Self, Sharon Adler, Nada Alachkar, Charles Alpers, Raed Bou Matar, Carmen Avila-Casado, Serena Bagnasco, Emily Brede, Elizabeth Brown, Daniel Cattran, Michael Choi, Katherine M. Dell, Darren Dewalt, Michelle Denburg, Ram Dukkipati, Fernando C. Fervenza, Crystal Gadegbeku, Patrick Gipson, Anny Gonzalez-Zea, Leah Hasely, Elizabeth Hendren, Sangeeta Hingorani, Michelle Hladunewich, Jonathan Hogan, Jean Hou, J. Ashley Jefferson, Kenar Jhaveri, Duncan B. Johnstone, Frederick Kaskel, Amy Kogan, Jeffrey Kopp, Richard Lafayette, Kevin V. Lemley, Laura Malaga-Dieguez, Kevin Meyers, Alicia Neu, Michelle Marie O'Shaughnessy, John F. O’Toole, Andrea Oliverio, Matthew Palmer, Rulan Parekh, Renee Pitter, Heather Reich, Kimberly Reidy, Helbert Rondon, Kamalanathan K. Sambandam, Matthew Sampson, John R. Sedor, Jeffrey Schelling, John C. Sperati, Agnes Swiatecka-Urban, Howard Trachtman, Meryl Waldman, Joseph Weisstuch, Roger Wiggins, David Williams, Cheryl Winkler, Suzanne Vento, Eric Young, Olga Zhdanova, Laura Barisoni, Charlotte Beil, Richard Eikstadt, Brenda Gillespie, John Graff, Stephen Hewitt, Peg Hill-Callahan, Margaret Helmuth, Chrysta Lienczewski, Sarah Mansfield, Laura Mariani, Keith McCullough, Nicholas Moore, Cynthia C. Nast, Melissa Sexton, Jonathan Troost, Matthew Wladkowski, Jarcy Zee, and Dawn Zinsser
- Subjects
0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Adolescent ,030232 urology & nephrology ,Renal function ,Article ,Nephropathy ,03 medical and health sciences ,0302 clinical medicine ,Focal segmental glomerulosclerosis ,Glomerulonephritis ,Membranous nephropathy ,Quality of life ,Internal medicine ,medicine ,Edema ,Humans ,Minimal change disease ,Longitudinal Studies ,Child ,Aged ,business.industry ,Middle Aged ,medicine.disease ,Obesity ,humanities ,030104 developmental biology ,Nephrology ,Quality of Life ,Anxiety ,Female ,Self Report ,medicine.symptom ,business - Abstract
There is scant literature describing the effect of glomerular disease on health-related quality of life (HRQOL). The Cure Glomerulonephropathy study (CureGN) is an international longitudinal cohort study of children and adults with four primary glomerular diseases (minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy). HRQOL is systematically assessed using items from the Patient-Reported Outcomes Measurement Informative System (PROMIS). We assessed the relationship between HRQOL and demographic and clinical variables in 478 children and 1115 adults at the time of enrollment into CureGN. Domains measured by PROMIS items included global assessments of health, mobility, anxiety, fatigue, and sleep impairment, as well as a derived composite measure incorporating all measured domains. Multivariable models were created that explained 7 to 32% of variance in HRQOL. Patient-reported edema consistently had the strongest and most robust association with each measured domain of HRQOL in multivariable analysis (adjusted β [95% CI] for composite PROMIS score in children, -5.2 [-7.1 to -3.4]; for composite PROMIS score in adults, -6.1 [-7.4 to -4.9]). Female sex, weight (particularly obesity), and estimated glomerular filtration rate were also associated with some, but not all, domains of HRQOL. Primary diagnosis, disease duration, and exposure to immunosuppression were not associated with HRQOL after adjustment. Sensitivity analyses and interaction testing demonstrated no significant association between disease duration or immunosuppression and any measured domain of HRQOL. Thus, patient-reported edema has a consistent negative association with HRQOL in patients with primary glomerular diseases, with substantially greater impact than other demographic and clinical variables.
- Published
- 2018
238. A protocol for single-cell transcriptomics from cryopreserved renal tissue and urine for the Accelerating Medicine Partnership (AMP) RA/SLE network
- Author
-
James A. Lederer, Edward P. Browne, Deepak A. Rao, David Wofsy, Jennifer H. Anolik, Matthias Kretzler, Patti Tosta, E. Steve Woodle, Nir Hacohen, Anne Davidson, Thomas Eisenhaure, Michael B. Brenner, Yanyan Liu, Dawn E. Smilek, David A. Hildeman, Celine C. Berthier, David J. Lieb, Betty Diamond, Arnon Arazi, and Adam Chicoine
- Subjects
030203 arthritis & rheumatology ,0303 health sciences ,Kidney ,Pathology ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Cell ,Lupus nephritis ,medicine.disease ,Cryopreservation ,Epithelium ,3. Good health ,Flow cytometry ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,medicine ,Cryopreserved Tissue ,business ,030304 developmental biology - Abstract
OBJECTIVEThere is a critical need to define the cells that mediate tissue damage in lupus nephritis. Here we aimed to establish a protocol to preserve lupus nephritis kidney biopsies and urine cell samples obtained at multiple clinical sites for subsequent isolation and transcriptomic analysis of single cells.METHODSFresh and cryopreserved kidney tissue from tumor nephrectomies and lupus nephritis kidney biopsies were disaggregated by enzymatic digestion. Cell yields and cell composition were assessed by flow cytometry. Transcriptomes of leukocytes and epithelial cells were evaluated by low-input and single cell RNA-seq.RESULTSCryopreserved kidney tissue from tumor nephrectomies and lupus nephritis biopsies can be thawed and dissociated to yield intact, viable leukocytes and epithelial cells. Cryopreservation of intact kidney tissue provides higher epithelial cell yields compared to cryopreservation of single cell suspensions from dissociated kidneys. Cell yields and flow cytometric cell phenotypes are comparable between cryopreserved kidney samples and paired kidney samples shipped overnight on wet ice. High-quality single cell and low-input transcriptomic data were generated from leukocytes from both cryopreserved lupus nephritis kidney biopsies and urine, as well as from a subset of kidney epithelial cells.CONCLUSIONThe AMP RA/SLE cryopreserved tissue analysis pipeline provides a method for centralized processing of lupus nephritis kidney biopsies and urine samples to generate robust transcriptomic analyses in multi-center studies.
- Published
- 2018
239. Renal Pre-Competitive Consortium (RPC
- Author
-
Mark, Tomilo, Heather, Ascani, Barbara, Mirel, Maria Chiara, Magnone, Carol Moreno, Quinn, Anil, Karihaloo, Kevin, Duffin, Uptal D, Patel, and Matthias, Kretzler
- Subjects
Drug Development ,Drug Industry ,Risk Factors ,Drug Design ,Systems Biology ,Disease Progression ,Animals ,Humans ,Kidney Diseases ,Molecular Targeted Therapy ,Biomarkers - Abstract
Despite significant effort, patients with kidney disease have not seen their outcomes improved significantly over the past two decades. This has motivated clinicians and researchers to consider alternative methods to identifying risk factors, disease progression markers, and effective therapies. Genome-scale data sets from patients with renal disease can be used to establish a platform to improve understanding of the molecular basis of disease; however, such studies require expertise and resources. To overcome these challenges, we formed an academic-industry consortium to share molecular target identification efforts and expertise across academia and the pharmaceutical industry. The Renal Pre-Competitive Consortium (RPC
- Published
- 2018
240. Single-cell analysis of progenitor cell dynamics and lineage specification in the human fetal kidney
- Author
-
Matthias Kretzler, Euisik Yoon, Jason R. Spence, Austin Kokoruda, Edgar A. Otto, Olga G. Troyanskaya, Jian Zhou, Cristina Cebrian, Zidong Zhang, Yu Chih Chen, and Rajasree Menon
- Subjects
0301 basic medicine ,Cell type ,Lineage (genetic) ,Mesenchyme ,Biology ,Kidney ,Transcriptome ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Fetus ,Single-cell analysis ,medicine ,Animals ,Humans ,Cell Lineage ,Progenitor cell ,Molecular Biology ,Gene Expression Profiling ,Stem Cells ,Gene Expression Regulation, Developmental ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Ureteric bud ,030217 neurology & neurosurgery ,Developmental Biology ,Signal Transduction - Abstract
The mammalian kidney develops through reciprocal interactions between the ureteric bud and the metanephric mesenchyme to give rise to the entire collecting system and the nephrons. Most of our knowledge of the developmental regulators driving this process arises from the study of gene expression and functional genetics in mice and other animal models. In order to shed light on human kidney development, we have used single-cell transcriptomics to characterize gene expression in different cell populations, and to study individual cell dynamics and lineage trajectories during development. Single-cell transcriptome analyses of 6414 cells from five individual specimens identified 11 initial clusters of specific renal cell types as defined by their gene expression profile. Further subclustering identifies progenitors, and mature and intermediate stages of differentiation for several renal lineages. Other lineages identified include mesangium, stroma, endothelial and immune cells. Novel markers for these cell types were revealed in the analysis, as were components of key signaling pathways driving renal development in animal models. Altogether, we provide a comprehensive and dynamic gene expression profile of the developing human kidney at the single-cell level.
- Published
- 2018
241. Systems biology approaches to identify disease mechanisms and facilitate targeted therapy in the management of glomerular disease
- Author
-
Habib Hamidi and Matthias Kretzler
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Systems biology ,medicine.medical_treatment ,Kidney Glomerulus ,030232 urology & nephrology ,Disease ,Article ,Targeted therapy ,03 medical and health sciences ,0302 clinical medicine ,Internal Medicine ,medicine ,Humans ,Multicenter Studies as Topic ,Renal Insufficiency ,Glomerular disease ,Precision Medicine ,Intensive care medicine ,business.industry ,Systems Biology ,Precision medicine ,3. Good health ,Clinical trial ,Subject-matter expert ,030104 developmental biology ,Nephrology ,Identification (biology) ,business - Abstract
PURPOSE OF REVIEW: Current clinical pathological classifications of glomerular diseases are inadequate at predicting patient disease progression or response to therapy. With the advent of precision medicine and its successes in oncology, it is important to understand if similar approaches in glomerular diseases can improve patient management. The purpose of this review is to summarize approaches to obtain comprehensive molecular profiles from human biopsies and utilize them to define the pathophysiology of glomerular failure. RECENT FINDINGS: Multicenter research networks have provided the framework to capture both prospective clinical disease course and patterns of end organ damage in biopsy cohorts. With these sample and data sets in hand, efforts are progressing towards molecular disease characterization, identification of novel prognostic marker, development of more precise clinical trials and discovery of predictive biomarkers to more effectively stratify patients to appropriate treatment regiments. Partnerships between academia, public funding agencies and private companies seek to improve timelines and maximize resources while also leveraging domain expertise in an integrated framework to holistically understand disease. SUMMARY: The application of system biology techniques within team science frameworks across disciplines and continents will seek to realize the impact of precision medicine to bring urgently needed novel therapeutic options to patients with glomerular disease.
- Published
- 2018
- Full Text
- View/download PDF
242. SUN-212 THE KIDNEY GENOME ATLAS: A WHOLE GENOME LANDSCAPE OF 5,800 INDIVIDUALS PROVIDES UNPRECEDENTED INSIGHTS INTO THE MOLECULAR MECHANISMS OF PROGRESSIVE KIDNEY DISEASES
- Author
-
R. Gbadegesin, W. Zhang, T. Soare, T. Tibbitts, L. Walsh, J. Wenke, A. Tebbe, Matthias Kretzler, P. Mundel, and G. Nadkarni
- Subjects
Kidney ,medicine.anatomical_structure ,Nephrology ,Atlas (anatomy) ,business.industry ,medicine ,Computational biology ,business ,Genome - Published
- 2019
243. Molecular studies of lupus nephritis kidneys
- Author
-
Weijia Zhang, Ramalingam Bethunaickan, Matthias Kretzler, Anne Davidson, Celine C. Berthier, and Ranjit Sahu
- Subjects
Pathology ,medicine.medical_specialty ,Immunology ,Lupus nephritis ,Inflammation ,Disease ,Biology ,Kidney ,Mice ,medicine ,Animals ,Humans ,Lupus Erythematosus, Systemic ,Endothelium ,Pathology, Molecular ,Endothelial dysfunction ,skin and connective tissue diseases ,Wound Healing ,Proteinuria ,Systemic lupus erythematosus ,Macrophages ,Systems Biology ,Dendritic Cells ,medicine.disease ,Lupus Nephritis ,Disease Models, Animal ,medicine.anatomical_structure ,Inflammation Mediators ,medicine.symptom ,Nephritis ,Biomarkers - Abstract
Lupus nephritis is a devastating complication of systemic lupus erythematosus (SLE) for which current therapies are insufficiently effective. Histologic evaluation of renal biopsies is a poor predictor of therapeutic response or outcome. Integrated immunologic, genomic and proteomic approaches may yield new insights into disease pathogenesis and thereby improve therapeutic strategies for lupus nephritis. Given the lack of sequential biopsies from humans, it also remains essential to study informative animal models of disease. Cross-species analyses can identify cells or pathways that are relevant to human disease and can be further studied in mouse models. Using a systems biology approach in which we compare molecular data from kidneys of three different mouse models of lupus nephritis with data from human lupus biopsies, we have found that inflammatory events escalate rapidly around the time of proteinuria onset. This is followed by hypoxia and metabolic stress, and by tubular and endothelial dysfunction. The failure of complete reversal of these abnormalities may increase the sensitivity of the kidney to further insult. We further found that renal macrophages and dendritic cells are key players in lupus nephritis both in mouse models and humans and that macrophages display a hybrid molecular profile that reflects incomplete resolution of inflammation and excessive tissue remodeling. Finally, our studies have suggested several new biomarkers for disease stage that can now be tested longitudinally in human SLE patients.
- Published
- 2015
244. Pro: 'The usefulness of biomarkers in glomerular diseases'. The problem: moving from syndrome to mechanism--individual patient variability in disease presentation, course and response to therapy
- Author
-
Matthias Kretzler and Laura H. Mariani
- Subjects
Transplantation ,medicine.medical_specialty ,Creatinine ,business.industry ,Renal function ,Precision medicine ,medicine.disease ,Clinical trial ,chemistry.chemical_compound ,chemistry ,Renal pathology ,Nephrology ,Disease Presentation ,Immunology ,medicine ,Medical diagnosis ,Intensive care medicine ,business ,Nephrotic syndrome - Abstract
The diagnosis and treatment decisions in glomerular disease are principally based on renal pathology and nonspecific clinical laboratory measurements such as serum creatinine and urine protein. Using these classification approaches, patients have marked variability in rate of progression and response to therapy, exposing a significant number of patients to toxicity without benefit. Additionally, clinical trials are at risk of not being able to detect an efficacious therapy in relevant subgroups as patients with shared clinical-pathologic diagnoses have heterogeneous underlying pathobiology. To change this treatment paradigm, biomarkers that reflect the molecular mechanisms underlying the clinical-pathologic diagnoses are needed. Recent progress to identify such biomarkers has been aided by advances in molecular profiling, large-scale data generation and multi-scalar data integration, including prospectively collected clinical data. This article reviews the evolving success stories in glomerular disease biomarkers across the genotype-phenotype continuum and highlights opportunities to transition to precision medicine in glomerular disease.
- Published
- 2015
245. The Metabolic Syndrome and Microvascular Complications in a Murine Model of Type 2 Diabetes
- Author
-
Junguk Hur, Carey Backus, John M. Hayes, Frank C. Brosius, Matthias Kretzler, Jacqueline R. Dauch, Eva L. Feldman, Lucy M. Hinder, and Subramaniam Pennathur
- Subjects
medicine.medical_specialty ,Complications ,Myelinated nerve fiber ,medicine.drug_class ,Endocrinology, Diabetes and Metabolism ,Neural Conduction ,Sural nerve ,Type 2 diabetes ,Weight Gain ,Nerve Fibers, Myelinated ,Mice ,Diabetic Neuropathies ,Sural Nerve ,Dorsal root ganglion ,Internal medicine ,Diabetes mellitus ,Internal Medicine ,Animals ,Hypoglycemic Agents ,Medicine ,Thiazolidinedione ,Triglycerides ,Metabolic Syndrome ,Nerve Fibers, Unmyelinated ,Pioglitazone ,business.industry ,medicine.disease ,Sciatic Nerve ,3. Good health ,Lipoproteins, LDL ,Disease Models, Animal ,Oxidative Stress ,Cholesterol ,Endocrinology ,medicine.anatomical_structure ,Diabetes Mellitus, Type 2 ,Thiazolidinediones ,Sciatic nerve ,business ,medicine.drug - Abstract
To define the components of the metabolic syndrome that contribute to diabetic polyneuropathy (DPN) in type 2 diabetes mellitus (T2DM), we treated the BKS db/db mouse, an established murine model of T2DM and the metabolic syndrome, with the thiazolidinedione class drug pioglitazone. Pioglitazone treatment of BKS db/db mice produced a significant weight gain, restored glycemic control, and normalized measures of serum oxidative stress and triglycerides but had no effect on LDLs or total cholesterol. Moreover, although pioglitazone treatment normalized renal function, it had no effect on measures of large myelinated nerve fibers, specifically sural or sciatic nerve conduction velocities, but significantly improved measures of small unmyelinated nerve fiber architecture and function. Analyses of gene expression arrays of large myelinated sciatic nerves from pioglitazone-treated animals revealed an unanticipated increase in genes related to adipogenesis, adipokine signaling, and lipoprotein signaling, which likely contributed to the blunted therapeutic response. Similar analyses of dorsal root ganglion neurons revealed a salutary effect of pioglitazone on pathways related to defense and cytokine production. These data suggest differential susceptibility of small and large nerve fibers to specific metabolic impairments associated with T2DM and provide the basis for discussion of new treatment paradigms for individuals with T2DM and DPN.
- Published
- 2015
246. MicroRNA-21 in Glomerular Injury
- Author
-
Jennifer Y. Lai, Thomas Tuschl, Ann Randolph, Christopher L. O’Connor, Frank C. Brosius, Regina N. Matar, Jiri Zavadil, Wenjun Ju, Markus Bitzer, Xiaohong Jing, Viji Nair, Daniel Briskin, Jinghui Luo, Matthias Kretzler, Robert G. Nelson, and Iddo Z. Ben-Dov
- Subjects
Adult ,Male ,medicine.medical_specialty ,Programmed cell death ,medicine.medical_treatment ,Kidney Glomerulus ,Apoptosis ,Smad Proteins ,Biology ,Podocyte ,Transforming Growth Factor beta1 ,Diabetic nephropathy ,Internal medicine ,medicine ,Albuminuria ,Animals ,Humans ,Diabetic Nephropathies ,Cells, Cultured ,Mice, Knockout ,Proteinuria ,Growth factor ,Glomerulosclerosis ,General Medicine ,Middle Aged ,medicine.disease ,Extracellular Matrix ,MicroRNAs ,Basic Research ,Endocrinology ,medicine.anatomical_structure ,Mice, Inbred DBA ,Nephrology ,Female ,medicine.symptom - Abstract
TGF-β(1) is a pleotropic growth factor that mediates glomerulosclerosis and podocyte apoptosis, hallmarks of glomerular diseases. The expression of microRNA-21 (miR-21) is regulated by TGF-β(1), and miR-21 inhibits apoptosis in cancer cells. TGF-β(1)-transgenic mice exhibit accelerated podocyte loss and glomerulosclerosis. We determined that miR-21 expression increases rapidly in cultured murine podocytes after exposure to TGF-β(1) and is higher in kidneys of TGF-β(1)-transgenic mice than wild-type mice. miR-21-deficient TGF-β(1)-transgenic mice showed increased proteinuria and glomerular extracellular matrix deposition and fewer podocytes per glomerular tuft compared with miR-21 wild-type TGF-β(1)-transgenic littermates. Similarly, miR-21 expression was increased in streptozotocin-induced diabetic mice, and loss of miR-21 in these mice was associated with increased albuminuria, podocyte depletion, and mesangial expansion. In cultured podocytes, inhibition of miR-21 was accompanied by increases in the rate of cell death, TGF-β/Smad3-signaling activity, and expression of known proapoptotic miR-21 target genes p53, Pdcd4, Smad7, Tgfbr2, and Timp3. In American-Indian patients with diabetic nephropathy (n=48), albumin-to-creatinine ratio was positively associated with miR-21 expression in glomerular fractions (r=0.6; P
- Published
- 2015
247. Localization of APOL1 Protein and mRNA in the Human Kidney
- Author
-
Matthias Kretzler, Barry I. Freedman, James A. Snipes, Mariana Murea, Dongmei Cheng, Gregory S. Shelness, Snezana Petrovic, Simon C. Satchell, Bernhard Banas, Allison Weckerle, Michael D. Ross, Lijun Ma, Martin R. Pollak, Moin A. Saleem, Lawrence L. Rudel, Peter W. Mathieson, Peter A. Antinozzi, Ashok K. Hemal, and John S. Parks
- Subjects
Cell type ,medicine.medical_specialty ,Biopsy ,Kidney Glomerulus ,In Vitro Techniques ,Biology ,Kidney ,Nephrectomy ,Cell Line ,Podocyte ,Kidney Tubules, Proximal ,Internal medicine ,Gene expression ,medicine ,Humans ,RNA, Messenger ,Cells, Cultured ,Messenger RNA ,Podocytes ,Epithelial Cells ,General Medicine ,Apolipoprotein L1 ,Molecular biology ,Basic Research ,Apolipoproteins ,Endocrinology ,medicine.anatomical_structure ,Microscopy, Fluorescence ,Nephrology ,Cell culture ,Mesangial Cells ,Synaptopodin ,Lipoproteins, HDL ,Immortalised cell line - Abstract
Although APOL1 gene variants are associated with nephropathy in African Americans, little is known about APOL1 protein synthesis, uptake, and localization in kidney cells. To address these questions, we examined APOL1 protein and mRNA localization in human kidney and human kidney-derived cell lines. Indirect immunofluorescence microscopy performed on nondiseased nephrectomy cryosections from persons with normal kidney function revealed that APOL1 protein was markedly enriched in podocytes (colocalized with synaptopodin and Wilms' tumor suppressor) and present in lower abundance in renal tubule cells. Fluorescence in situ hybridization detected APOL1 mRNA in glomeruli (podocytes and endothelial cells) and tubules, consistent with endogenous synthesis in these cell types. When these analyses were extended to renal-derived cell lines, quantitative RT-PCR did not detect APOL1 mRNA in human mesangial cells; however, abundant levels of APOL1 mRNA were observed in proximal tubule cells and glomerular endothelial cells, with lower expression in podocytes. Western blot analysis revealed corresponding levels of APOL1 protein in these cell lines. To explain the apparent discrepancy between the marked abundance of APOL1 protein in kidney podocytes observed in cryosections versus the lesser abundance in podocyte cell lines, we explored APOL1 cellular uptake. APOL1 protein was taken up readily by human podocytes in vitro but was not taken up efficiently by mesangial cells, glomerular endothelial cells, or proximal tubule cells. We hypothesize that the higher levels of APOL1 protein in human cryosectioned podocytes may reflect both endogenous protein synthesis and APOL1 uptake from the circulation or glomerular filtrate.
- Published
- 2015
248. Integrative Biology of Diabetic Kidney Disease
- Author
-
Jennifer L. Harder, Matthias Kretzler, and Jeffrey B. Hodgin
- Subjects
0303 health sciences ,Diabetic kidney ,business.industry ,Systems biology ,030232 urology & nephrology ,Review ,Disease ,medicine.disease ,Bioinformatics ,3. Good health ,Diabetic nephropathy ,03 medical and health sciences ,0302 clinical medicine ,Medicine ,Integrative biology ,business ,030304 developmental biology - Abstract
Background: The leading cause of end-stage renal disease in the US is diabetic kidney disease (DKD). Despite significant efforts to improve outcomes in DKD, the impact on disease progression has been disappointing. This has prompted clinicians and researchers to search for alternative approaches to identify persons at risk, and to search for more effective therapies to halt progression of DKD. The identification of novel therapies is critically dependent on a more comprehensive understanding of the pathophysiology of DKD, specifically at the molecular level. A more expansive and exploratory view of DKD is needed to complement more traditional research approaches that have focused on single molecules. Summary: In recent years, sophisticated research methodologies have emerged within systems biology that should allow for a more comprehensive disease definition of DKD. Systems biology provides an interdisciplinary approach to describe complex interactions within biological systems, including how these interactions influence systems' functions and behaviors. Computational modeling of large, system-wide, quantitative data sets is used to generate molecular interaction pathways, such as metabolic and cell signaling networks. Key Messages: Importantly, the interpretation of data generated by systems biology tools requires integration with enhanced clinical research data and validation using model systems. Such an integrative biological approach has already generated novel insights into pathways and molecules involved in DKD. In this review, we highlight recent examples of how combining systems biology with traditional clinical and model research efforts results in an integrative biology approach that significantly adds to the understanding of the complex pathophysiology of DKD.
- Published
- 2015
249. Integrative Biology Identifies Shared Transcriptional Networks in CKD
- Author
-
Felix Eichinger, Ann Randolph, Clemens D. Cohen, Crystal A. Gadegbeku, Benjamin J. Keller, Jennifer Hawkins, Sebastian Martini, Carsten A. Böger, Viji Nair, Caroline S. Fox, C-Probe Cohort, and Matthias Kretzler
- Subjects
Adult ,Male ,Candidate gene ,Transcription, Genetic ,Lupus nephritis ,Gene regulatory network ,Single-nucleotide polymorphism ,Genome-wide association study ,Context (language use) ,Biology ,Polymorphism, Single Nucleotide ,Transcriptome ,Young Adult ,Databases, Genetic ,medicine ,Humans ,Gene Regulatory Networks ,Renal Insufficiency, Chronic ,Aged ,Genetic association ,Genetics ,General Medicine ,Middle Aged ,medicine.disease ,Nephrology ,North America ,Disease Progression ,Female ,Genome-Wide Association Study ,Signal Transduction - Abstract
A previous meta-analysis of genome-wide association data by the Cohorts for Heart and Aging Research in Genomic Epidemiology and CKDGen consortia identified 16 loci associated with eGFR. To define how each of these single-nucleotide polymorphisms (SNPs) could affect renal function, we integrated GFR-associated loci with regulatory pathways, producing a molecular map of CKD. In kidney biopsy specimens from 157 European subjects representing nine different CKDs, renal transcript levels for 18 genes in proximity to the SNPs significantly correlated with GFR. These 18 genes were mapped into their biologic context by testing coregulated transcripts for enriched pathways. A network of 97 pathways linked by shared genes was constructed and characterized. Of these pathways, 56 pathways were reported previously to be associated with CKD; 41 pathways without prior association with CKD were ranked on the basis of the number of candidate genes connected to the respective pathways. All pathways aggregated into a network of two main clusters comprising inflammation- and metabolism-related pathways, with the NRF2-mediated oxidative stress response pathway serving as the hub between the two clusters. In all, 78 pathways and 95% of the connections among those pathways were verified in an independent North American biopsy cohort. Disease-specific analyses showed that most pathways are shared between sets of three diseases, with closest interconnection between lupus nephritis, IgA nephritis, and diabetic nephropathy. Taken together, the network integrates candidate genes from genome-wide association studies into their functional context, revealing interactions and defining established and novel biologic mechanisms of renal impairment in renal diseases.
- Published
- 2014
250. A reassessment of soluble urokinase-type plasminogen activator receptor in glomerular disease
- Author
-
Debbie S. Gipson, Robert Weyant, Jidong Zhang, Deepak Nihalani, Matthias Kretzler, Laura H. Mariani, Peter X.-K. Song, Crystal A. Gadegbeku, Lawrence B. Holzman, Shiv Kapoor, Joann M. Spinale, Hetty N. Wong, and Jonathan P. Troost
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,Renal function ,Mice, Transgenic ,urologic and male genital diseases ,Gastroenterology ,Glomerulonephritis, Membranous ,Article ,Receptors, Urokinase Plasminogen Activator ,chemistry.chemical_compound ,Mice ,Young Adult ,Glomerulonephritis ,Internal medicine ,medicine ,Albuminuria ,Animals ,Humans ,Prospective Studies ,Child ,Urokinase ,Creatinine ,Proteinuria ,business.industry ,Glomerulosclerosis, Focal Segmental ,Nephrosis, Lipoid ,Glomerulosclerosis ,Glomerulonephritis, IGA ,Middle Aged ,medicine.disease ,Recombinant Proteins ,Urokinase receptor ,Endocrinology ,SuPAR ,chemistry ,Nephrology ,Female ,medicine.symptom ,business ,Biomarkers ,medicine.drug ,Glomerular Filtration Rate - Abstract
It has been suggested that soluble urokinase receptor (suPAR) is a causative circulating factor for and a biomarker of focal and segmental glomerulosclerosis (FSGS). Here we undertook validation of these assumptions in both mouse and human models. Injection of recombinant suPAR in wild-type mice did not induce proteinuria within 24 hours. Moreover, a disease phenotype was not seen in an inducible transgenic mouse model that maintained elevated suPAR concentrations for 6 weeks. Plasma and urine suPAR concentrations were evaluated as clinical biomarkers in 241 patients with glomerular disease from the prospective, longitudinal multi-center observational NEPTUNE cohort. The serum suPAR concentration at baseline inversely correlated with estimated glomerular filtration rate (eGFR) and the urine suPAR/creatinine ratio positively correlated with the urine protein/creatinine ratio. After adjusting for eGFR and urine protein, neither the serum nor urine suPAR level was an independent predictor of FSGS histopathology. A multivariable mixed-effects model of longitudinal data evaluated the association between the change in serum suPAR concentration from baseline with eGFR. After adjusting for baseline suPAR concentration, age, gender, proteinuria and time, the change in suPAR from baseline was associated with eGFR, but this association was not different for patients with FSGS as compared to other diagnoses. Thus, these results do not support a pathological role for suPAR in FSGS.
- Published
- 2014
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.