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BACKGROUND: Although VCAM-1 (vascular cell adhesion molecule-1) and ICAM-1 (intercellular adhesion molecule-1) have been associated with incident heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF), the associations of VCAM-1 and ICAM-1 with sensitive measures of cardiac structure/function are unclear. The objective of this study is to evaluate associations between VCAM-1, ICAM-1, and measures of cardiac structure and function as potential pathways through which cellular adhesion molecules promote HFpEF and AF risk. METHODS AND RESULTS: In MESA (Multi-Ethnic Study of Atherosclerosis), we evaluated the associations of circulating VCAM-1 and ICAM-1 at examination 2 (2002-2004) with measures of cardiac structure/function on cardiac magnetic resonance imaging at examination 5 (2010-2011) after multivariable adjustment. Mediation analysis of left atrial (LA) strain on the association between VCAM-1 or ICAM-1 and AF or HFpEF was also performed. Overall, 2304 individuals (63±10 years; 47% men) with VCAM-1 or ICAM-1, cardiac magnetic resonance imaging, and covariate data were included in analysis. Higher VCAM-1 and ICAM-1 were associated with lower LA peak longitudinal strain and worse global circumferential left ventricular strain but were not associated with left ventricular myocardial scar or interstitial fibrosis. Lower LA peak longitudinal strain mediated 8% (95% CI, 2-30) of the relationship between VCAM-1 and HFpEF and 9% (95% CI, 2-21) of the relationship between VCAM-1 and AF. CONCLUSIONS: Higher VCAM-1 and ICAM-1 were associated with lower LA function and left ventricular systolic function but were not associated with myocardial scar or interstitial fibrosis. VCAM-1 and ICAM-1 may promote HFpEF and AF risk through impaired LA reservoir function.

Chronic kidney disease (CKD) is the progressive loss of kidney function/structure over a period of at least 3 months. It is characterised histologically by the triad of cell loss, inflammation and fibrosis. This literature review focuses on the forms of cell death that trigger downstream inflammation and fibrosis, collectively called regulated cell death (RCD) pathways. Discrete forms of RCD have emerged as central mediators of CKD pathology. In particular, pathways of regulated necrosis – including mitochondrial permeability transition pore (mPTP)-mediated necrosis, necroptosis, ferroptosis and pyroptosis – have been shown to mediate kidney pathology directly or through the release of danger signals that trigger a pro-inflammatory response, further amplifying tissue injury in a cellular process called necroinflammation. Despite accumulating evidence in pre-clinical models, no clinical studies have yet targeted these RCD modes in human CKD. The review summarizes recent advances in our understanding of RCD pathways in CKD, looks at inter-relations between the pathways (with the emphasis on propagation of death signals) and the evidence for therapeutic targeting of molecules in the RCD pathways to prevent or treat CKD. [ABSTRACT FROM AUTHOR]

Objectives: This study was performed to investigate the relationship between hemoglobin, albumin, lymphocyte and platelet (HALP) score and Oxford classification severe tubular atrophy/interstitial fibrosis (T2) in IgA nephropathy (IgAN). Methods: The clinical data and pathological findings of patients with IgA nephropathy diagnosed through renal biopsy at Hangzhou Hospital of Traditional Chinese Medicine between June 1, 2019 and May 31, 2022 were retrospectively collected and analyzed. The HALP score was calculated as hemoglobin (g/L) × albumin (g/L) × lymphocytes (/L)/ platelets (/L). According to the quartile of HALP scores in the study population, the subjects were divided into four groups: Quartile 1 (< 30.72), Quartile 2 (30.72–39.97), Quartile 3 (39.97–53.25) and Quartile 4(> 53.25). According to the extent of tubular atrophy/interstitial fibrosis, patients were categorized into mild to moderate injury (T0 + T1, ≤ 50%) and severe injury (T2, > 50%). The relationship between HALP score and severe tubular atrophy/interstitial fibrosis was investigated using Spearman's rank correlation coefficient, logistic regression analysis, restricted cubic splines (RCS), and receiver operating characteristic (ROC) curve analysis. Results: A total of 895 patients diagnosed with IgAN were included in this study, with an average age of 40.97 ± 12.261 years. Among them, 384 (42.9%) were male and 61 (6.8%) exhibited severe tubular atrophy/interstitial fibrosis. Multifactorial logistic regression analysis revealed that HALP independently influenced T2 (OR = 0.952, 95% CI 0.923–0.982, P = 0.002). Compared to Quartile 1, patients in Quartile 4 exhibited a significantly reduced risk of T2 (OR = 0.205, 95% CI 0.058–0.722, P = 0.014). Restricted cubic splines analysis revealed a linear inverse association between HALP and T2 risk (nonlinear P = 0.896). Furthermore, the receiver operating characteristic curve demonstrated that HALP possessed predictive value for T2 (AUC = 0.693, Jorden index = 0.324), and the cutoff value of HALP score is 36.54. Conclusions: The risk of severe renal tubular atrophy/interstitial fibrosis is higher in IgAN patients with low HALP. HALP greater than 36.54 May reduce the risk of severe tubular atrophy/interstitial fibrosis. [ABSTRACT FROM AUTHOR]

Background: The Myositis Interstitial Lung Disease Nintedanib Trial (MINT) is a hybrid trial, which is enrolling patients both at local sites and remotely via a decentralised site. The trial will investigate the efficacy and safety of nintedanib in patients with progressive myositis-associated interstitial lung disease (MA-ILD). Methods/Design: MINT is an exploratory, prospective randomised placebo-controlled trial. Eligible patients will have myositis and evidence of fibrosing ILD on high-resolution computed tomography (HRCT), be taking standard of care medications for myositis, and meet criteria for ILD progression within the prior 24 months based on decline in FVC, worsened fibrosis on HRCT, and/or worsened dyspnoea. Patients will be randomised 1:1 to receive nintedanib 150 mg twice daily or placebo for 12 weeks then open-label nintedanib for 12 weeks. Patients will be enrolled at local sites and a decentralised site. Most study visits will be completed remotely using telemedicine or digital health technologies. The primary endpoint is the change in Living with Pulmonary Fibrosis (L-PF) questionnaire dyspnoea domain score at week 12. Other endpoints include changes in other L-PF questionnaire domains, lung function, imaging, and physical activity, and assessment of adverse events. Data collected using remote versus clinic enrolment, and using home versus clinic spirometry, will be compared. Discussion: MINT is an innovative, hybrid trial that will evaluate the effects of nintedanib on symptoms, quality of life, and ILD progression in patients with progressive MA-ILD and provide valuable information on the utility of decentralised recruitment and remote data collection in clinical trials. Trial registration: Clinicaltrials.gov NCT05799755 (date of registration: 05/04/2023). [ABSTRACT FROM AUTHOR]

Abstract Objectives This study was performed to investigate the relationship between hemoglobin, albumin, lymphocyte and platelet (HALP) score and Oxford classification severe tubular atrophy/interstitial fibrosis (T2) in IgA nephropathy (IgAN). Methods The clinical data and pathological findings of patients with IgA nephropathy diagnosed through renal biopsy at Hangzhou Hospital of Traditional Chinese Medicine between June 1, 2019 and May 31, 2022 were retrospectively collected and analyzed. The HALP score was calculated as hemoglobin (g/L) × albumin (g/L) × lymphocytes (/L)/ platelets (/L). According to the quartile of HALP scores in the study population, the subjects were divided into four groups: Quartile 1 ( 53.25). According to the extent of tubular atrophy/interstitial fibrosis, patients were categorized into mild to moderate injury (T0 + T1, ≤ 50%) and severe injury (T2, > 50%). The relationship between HALP score and severe tubular atrophy/interstitial fibrosis was investigated using Spearman's rank correlation coefficient, logistic regression analysis, restricted cubic splines (RCS), and receiver operating characteristic (ROC) curve analysis. Results A total of 895 patients diagnosed with IgAN were included in this study, with an average age of 40.97 ± 12.261 years. Among them, 384 (42.9%) were male and 61 (6.8%) exhibited severe tubular atrophy/interstitial fibrosis. Multifactorial logistic regression analysis revealed that HALP independently influenced T2 (OR = 0.952, 95% CI 0.923–0.982, P = 0.002). Compared to Quartile 1, patients in Quartile 4 exhibited a significantly reduced risk of T2 (OR = 0.205, 95% CI 0.058–0.722, P = 0.014). Restricted cubic splines analysis revealed a linear inverse association between HALP and T2 risk (nonlinear P = 0.896). Furthermore, the receiver operating characteristic curve demonstrated that HALP possessed predictive value for T2 (AUC = 0.693, Jorden index = 0.324), and the cutoff value of HALP score is 36.54. Conclusions The risk of severe renal tubular atrophy/interstitial fibrosis is higher in IgAN patients with low HALP. HALP greater than 36.54 May reduce the risk of severe tubular atrophy/interstitial fibrosis.

Abstract Background The Myositis Interstitial Lung Disease Nintedanib Trial (MINT) is a hybrid trial, which is enrolling patients both at local sites and remotely via a decentralised site. The trial will investigate the efficacy and safety of nintedanib in patients with progressive myositis-associated interstitial lung disease (MA-ILD). Methods/Design MINT is an exploratory, prospective randomised placebo-controlled trial. Eligible patients will have myositis and evidence of fibrosing ILD on high-resolution computed tomography (HRCT), be taking standard of care medications for myositis, and meet criteria for ILD progression within the prior 24 months based on decline in FVC, worsened fibrosis on HRCT, and/or worsened dyspnoea. Patients will be randomised 1:1 to receive nintedanib 150 mg twice daily or placebo for 12 weeks then open-label nintedanib for 12 weeks. Patients will be enrolled at local sites and a decentralised site. Most study visits will be completed remotely using telemedicine or digital health technologies. The primary endpoint is the change in Living with Pulmonary Fibrosis (L-PF) questionnaire dyspnoea domain score at week 12. Other endpoints include changes in other L-PF questionnaire domains, lung function, imaging, and physical activity, and assessment of adverse events. Data collected using remote versus clinic enrolment, and using home versus clinic spirometry, will be compared. Discussion MINT is an innovative, hybrid trial that will evaluate the effects of nintedanib on symptoms, quality of life, and ILD progression in patients with progressive MA-ILD and provide valuable information on the utility of decentralised recruitment and remote data collection in clinical trials. Trial registration Clinicaltrials.gov NCT05799755 (date of registration: 05/04/2023).

Objective To evaluate the risk of end-stage kidney disease (ESKD) in LN patients using tubulointerstitial lesion scores. Methods Clinical profiles and histopathological presentations of 151 biopsy-proven LN patients were retrospectively examined. Risk factors of ESKD based on characteristics and scoring of their tubulointerstitial lesions [e.g. interstitial inflammation (II), tubular atrophy (TA) and interstitial fibrosis (IF)] were analysed. Results The mean age of 151 LN patients was 36 years old, and 136 (90.1%) were female. The LN cases examined included: class I/II (n  = 3, 2%), class III/IV (n  = 119, 78.8%), class V (n  = 23, 15.2%) and class VI (n  = 6, 4.0%). The mean serum creatinine level was 1.4 mg/dl. Tubulointerstitial lesions were recorded in 120 (79.5%) patients. Prior to receiving renal biopsy, nine (6.0%) patients developed ESKD. During the follow-up period (mean, 58 months), an additional 47 patients (31.1%) progressed to ESKD. Multivariate analyses identified serum creatinine [hazard ratio (HR): 1.7, 95% CI: 1.42–2.03, P   <  0.001] and IF (HR: 3.2, 95% CI: 1.58–6.49, P   =  0.001) as independent risk factors of ESKD. Kaplan–Meier analysis further confirmed a heightened risk of ESKD associated with IF. Conclusion Tubulointerstitial involvement is commonly observed in the histopathological presentation of LN. However, IF, rather than II or TA, was found to increase the risk of ESKD in our cohort. Therefore, to predict renal outcome in LN patients prior to adjusting immunosuppressive treatment, the degree of IF should be reviewed. [ABSTRACT FROM AUTHOR]

Purpose. Interstitial fibrosis in papillary thyroid microcarcinoma is a subject which is under-investigated. The aim of this study is to determine the relationship between interstitial fibrosis, the subtypes of papillary microcarcinoma, and the established prognostic factors. Material and Methods. A total of 75 patients diagnosed with papillary microcarcinoma of the thyroid from January 2011 to December 2020 have been evaluated retrospectively, using demographic features, tumor size, subtype of the tumor, surgical margin status, unifocality, lymphovascular invasion, extracapsular spread and lymph node metastasis as parameters. Hematoxylin and eosin slides were reviewed for interstitial fibrosis. Results. The study includes 13 males and 62 females, in a total of 75 patients. There were 51 patients (68%) with interstitial fibrosis and 24 (32%) patients without interstitial fibrosis. Among them, 45 (60%) were classic, 27 (36%) were follicular variant and 3 (4%) were other subtypes. Interstitial fibrosis is significantly associated with bilaterality (p = 0.023), multifocality (p = 0.004), capsule invasion (p < 0.001) and lymph node metastasis (p = 0.043). Evaluation of tumor sub groups showed significant increased risk of lymphovascular invasion in the follicular variant (p = 0.019). Conclusion. Although the relationship of interstitial fibrosis and prognosis of other cancer types has been discussed, there are few studies in the literature regarding its effect on the prognosis of papillary microcarcinoma. Our results show that interstitial fibrosis can be used as a risk factor. However, new studies are needed to clearly reveal the physiopathology of interstitial fibrosis and its effect on tumorigenesis. [ABSTRACT FROM AUTHOR]

Fibrosis is a marker of chronic kidney disease (CKD) and consists of the accumulation of the extracellular matrix (ECM) components, causing the progressive deterioration of kidney function. Human liver stem cells (HLSCs) have anti-fibrotic activity, and HLSC-derived extracellular vesicles (EVs) mediate this effect. Herein, we evaluated the ability of HLSC-EVs to reverse renal and cardiac alterations in a murine model of partial nephrectomy (PNx) that mimics human CKD development. Furthermore, we investigated the contribution of extracellular matrix remodeling-related proteases to the anti-fibrotic effect of HLSC-EVs. PNx was performed by ligation of both poles of the left kidney, followed one week later by the removal of the right kidney. EV treatment started 4 weeks after the nephrectomy, when renal and cardiac alternations were already established, and mice were sacrificed at week eight. HLSC-EV treatment improved renal function and morphology, significantly decreasing interstitial fibrosis, glomerular sclerosis, and capillary rarefaction. This improvement was confirmed by the decreased expression of pro-fibrotic genes. Moreover, EV treatment improved cardiac function and reduced cardiac fibrosis. HLSC-EVs shuttled different proteases with ECM remodeling activity, and matrix metalloproteinase 1 (MMP-1) was involved in their anti-fibrotic effect on renal tissue. HLSC-EV treatment interferes with CKD development and ameliorates cardiomyopathy in PNx mice. [ABSTRACT FROM AUTHOR]

Background This study aims to evaluate the clinical application value of ultrasound viscoelastic imaging in noninvasive quantitative assessment of chronic kidney disease (CKD).Methods A total of 332 patients with CKD and 190 healthy adults as a control group were prospectively enrolled. Before kidney biopsy, ultrasound viscoelastic imaging was performed to measure the mean stiffness value (Emean), mean viscosity coefficient (Vmean), and mean dispersion coefficient (Dmean) of the renal. CKD patients were divided into three groups based on estimated glomerular filtration rate. The differences in clinic, pathology, ultrasound image parameters between the control and patient groups, or among different CKD groups were compared. The correlation between viscoelastic parameters and pathology were analyzed.Results Emean, Vmean, and Dmean in the control group were less than the CKD group (p 6.61 kPa, Vmean > 1.86 Pa·s, or Dmean > 7.51 m/s/kHz may suggest renal dysfunction. Combining Vmean, Dmean, and Emean can improve the efficiency of identifying CKD.

BackgroundMore evidence have shown that the combination of immune and inflammatory mechanism was critical in diabetic nephropathy (DN). However, the relationship between CD4+ T cells and the development of DN is still unclear. Therefore, this study will focus on this issue from the perspective of clinicopathology.MethodsFrom September 2019 to December 2022, a total of 112 adult patients with DN were enrolled in the study. According to the density of CD4+ T cell infiltration based on immunostaining, the patients were divided into high-CD4 group (56 patients) and low-CD4 group (56 patients). Another 25 diabetic patients with minimal change disease (non-diabetic nephropathy, NDN) was reviewed as control group in clinical and molecular analysis. The clinical parameters, morphological features, and molecular characteristics were compared. The predictive value of CD4+ T cells for DN prognosis was also investigated.ResultsDN patients in the high-CD4 group suffered from higher proteinuria and lower estimated glomerular filtration rate (eGFR) level than those in the low-CD4 group and NDN patients. Renal biopsy in the high-CD4 group presented with more severe glomerular lesions, higher density of interstitial inflammation, and more severe tubular atrophy/interstitial fibrosis than in the low-CD4 group. Multivariate logistic analysis indicated that the density of CD4+ T cell infiltration could independently predict the severity of tubular atrophy/interstitial fibrosis. In addition, more severe mitochondrial damage of renal tubular epithelial cells and a more obvious expression of Bcl6, IL-6, STAT3, and TGFβ1 were observed in DN patients of the high-CD4 group, indicating the possible mechanism of CD4+ T cells involving the progression of DN. Multivariate Cox regression analysis revealed that a higher intensity of interstitial CD4+ T cell deposition remained as an independent predictor of the double endpoint with doubling of baseline serum creatinine or end-stage renal disease.ConclusionThe high density of CD4+ T cell infiltration was associated with renal function decline and severity of renal lesions and predicted poor renal survival for DN patients.

Chronic kidney disease (CKD) is the progressive loss of kidney function/structure over a period of at least 3 months. It is characterised histologically by the triad of cell loss, inflammation and fibrosis. This literature review focuses on the forms of cell death that trigger downstream inflammation and fibrosis, collectively called regulated cell death (RCD) pathways. Discrete forms of RCD have emerged as central mediators of CKD pathology. In particular, pathways of regulated necrosis – including mitochondrial permeability transition pore (mPTP)-mediated necrosis, necroptosis, ferroptosis and pyroptosis – have been shown to mediate kidney pathology directly or through the release of danger signals that trigger a pro-inflammatory response, further amplifying tissue injury in a cellular process called necroinflammation. Despite accumulating evidence in pre-clinical models, no clinical studies have yet targeted these RCD modes in human CKD. The review summarizes recent advances in our understanding of RCD pathways in CKD, looks at inter-relations between the pathways (with the emphasis on propagation of death signals) and the evidence for therapeutic targeting of molecules in the RCD pathways to prevent or treat CKD.

BackgroundThe MUC5B promoter variant (rs35705950) and telomere length are linked to pulmonary fibrosis and CT-based qualitative assessments of interstitial abnormalities, but their associations with longitudinal quantitative changes of the lung interstitium among community-dwelling adults are unknown.MethodsWe used data from participants in the Multi-Ethnic Study of Atherosclerosis with high-attenuation areas (HAAs, Examinations 1-6 (2000-2018)) and MUC5B genotype (n=4552) and telomere length (n=4488) assessments. HAA was defined as the per cent of imaged lung with attenuation of -600 to -250 Hounsfield units. We used linear mixed-effects models to examine associations of MUC5B risk allele (T) and telomere length with longitudinal changes in HAAs. Joint models were used to examine associations of longitudinal changes in HAAs with death and interstitial lung disease (ILD).ResultsThe MUC5B risk allele (T) was associated with an absolute change in HAAs of 2.60% (95% CI 0.36% to 4.86%) per 10 years overall. This association was stronger among those with a telomere length below an age-adjusted percentile of 5% (p value for interaction=0.008). A 1% increase in HAAs per year was associated with 7% increase in mortality risk (rate ratio (RR)=1.07, 95% CI 1.02 to 1.12) for overall death and 34% increase in ILD (RR=1.34, 95% CI 1.20 to 1.50). Longer baseline telomere length was cross-sectionally associated with less HAAs from baseline scans, but not with longitudinal changes in HAAs.ConclusionsLongitudinal increases in HAAs were associated with the MUC5B risk allele and a higher risk of death and ILD.

This study aims to analyze the vein of Marshall (VOM) in human autopsy hearts and its correlation with clinical data to elucidate the morphological substrates of atrial fibrillation (AF) and other cardiac diseases. Twenty‐three adult autopsy hearts were studied, assessing autonomic nerves by immunohistochemistry with tyrosine hydroxylase (sympathetic nerves), choline acetyltransferase (parasympathetic nerves), growth‐associated protein 43 (neural growth), and S100 (general neural marker) antibodies. Interstitial fibrosis was assessed by Masson trichrome staining. Measurements were conducted via morphometric software. The results were correlated with clinical data. Sympathetic innervation was abundant in all VOM‐adjacent regions. Subjects with a history of AF, cardiovascular cause of death, and histologically verified myocardial infarction had increased sympathetic innervation and neural growth around the VOM at the mitral isthmus. Interstitial fibrosis increased with age and heart weight was associated with AF and cardiovascular cause of death. This study increases our understanding of the cardiac autonomic innervation in the VOM area in various diseases, offering implications for the development of new therapeutic approaches targeting the autonomic nervous system. [ABSTRACT FROM AUTHOR]

Background: Diabetic nephropathy (DN) is a diabetic complication. LncRNAs are reported to participate in the pathophysiology of DN. Here, the function and mechanism of lncRNA small nucleolar RNA host gene14 (SNHG14) in DN were explored. Methods: Streptozotocin (STZ)‐induced DN mouse models and high glucose (HG)‐treated human mesangial cells (MCs) were used to detect SNHG14 expression. SNHG14 silencing plasmids were applied to examine the function of SNHG14 on proliferation and fibrosis in HG‐treated MCs. Potential targets of SNHG14 were predicted using bioinformatics tools and verified by luciferase reporter, RNA pulldown, and northern blotting assays. The functional role of SNHG14 in DN in vivo was detected by injection with adenoviral vector carrying sh‐SNHG14 into DN mice. Serum creatinine, blood urea nitrogen, blood glucose, 24‐h proteinuria, relative kidney weight, and renal pathological changes were examined in DN mice. Results: SNHG14 expression was elevated in the kidneys of DN mice and HG‐treated MCs. SNHG14 silencing inhibited proliferation and fibrosis of HG‐stimulated MCs. SNHG14 bound to miR‐30e‐5p to upregulate SOX4 expression. In rescue assays, SOX4 elevation diminished the effects of SNHG14 silencing in HG‐treated MCs, and SOX4 silencing reversed the effects of SNHG14 overexpression. In in vivo studies, SNHG14 downregulation significantly ameliorated renal injuries and renal interstitial fibrosis in DN mice. Conclusions: SNHG14 silencing attenuates kidney injury in DN mice and reduces proliferation and fibrotic phenotype of HG‐stimulated MCs via the miR‐30e‐5p/SOX4 axis. [ABSTRACT FROM AUTHOR]

Introduction: The relevance of tubulo‐interstitial involvement for kidney prognosis has recently been emphasized, but validated biomarkers for predicting histology are still lacking. The aim of our study was to evaluate different serum and urinary markers of tubular damage in patients with lupus nephritis (LN) and to correlate them with kidney histopathology. Methods: A single‐center retrospective study was conducted from January 2016 to December 2021. Serum and urine samples were collected on the same day of kidney biopsy and correlated with histologic data from a cohort of 15 LN patients. We analyzed the following urinary markers, adjusted for urine creatinine: beta 2‐microglobulin, alpha 1‐microglobulin, NGAL, uKIM‐1, MCP‐1, uDKK‐3, and uUMOD. The serum markers sKIM‐1 and sUMOD were also analyzed. Results: A positive and strong correlation was observed between the degree of interstitial fibrosis (rho = 0.785, p =.001) and tubular atrophy (rho = 0.781, p =.001) and the levels of uDKK3. uUMOD also showed an inverse and moderate correlation with interstitial fibrosis (rho = −0.562, p =.037) and tubular atrophy (rho = −0.694, p =.006). Patients with >10% cortical interstitial inflammation had higher levels of uKIM‐1 [4.9 (3.9, 5.5) vs. 0.8 (0.6, 1.5) mcg/mg, p =.001], MCP‐1 [3.8 (2. 3, 4.2) vs. 0.7 (0.3, 1.2) mcg/mg, p =.001], sKIM‐1 [9.2 (5.9, 32.7) vs. 1.4 (0, 3.5) pg/mL, p =.001], and lower sUMOD [8.7 (0, 39.7) vs. 46.1 (35.7, 53) ng/mL, p =.028]. Conclusion: The use of specific urinary and serum biomarkers of tubular dysfunction or injury may help to predict certain histologic parameters in LN patients. [ABSTRACT FROM AUTHOR]

Background Proteinuria is not only a biomarker of chronic kidney disease (CKD) but also a driver of CKD progression. The aim of this study was to evaluate serum and urinary tubular biomarkers in patients with biopsied proteinuric kidney disease and to correlate them with histology and kidney outcomes. Methods A single-center retrospective study was conducted on a cohort of 156 patients from January 2016 to December 2021. The following urinary and serum biomarkers were analyzed on the day of kidney biopsy: beta 2 microglobulin (β2-mcg), alpha 1 microglobulin (α1-mcg), neutrophil gelatinase-associated lipocalin (NGAL), urinary kidney injury molecule-1 (uKIM-1), monocyte chemoattractant protein-1 (MCP-1), urinary Dickkopf-3 (uDKK3), uromodulin (urinary uUMOD), serum kidney injury molecule-1 (sKIM-1) and serum uromodulin (sUMOD). A composite outcome of kidney progression or death was recorded during a median follow-up period of 26 months. Results Multivariate regression analysis identified sUMOD (β–0.357, P  < .001) and uDKK3 (β 0.483, P  < .001) as independent predictors of interstitial fibrosis, adjusted for age, estimated glomerular filtration rate (eGFR) and log proteinuria. Elevated levels of MCP-1 [odds ratio 15.61, 95% confidence interval (CI) 3.52–69.20] were associated with a higher risk of cortical interstitial inflammation >10% adjusted for eGFR, log proteinuria and microhematuria. Upper tertiles of uDKK3 were associated with greater eGFR decline during follow-up. Although not a predictor of the composite outcome, doubling of uDKK3 was a predictor of kidney events (hazard ratio 2.26, 95% CI 1.04–4.94) after adjustment for interstitial fibrosis, eGFR and proteinuria. Conclusions Tubular markers may have prognostic value in proteinuric kidney disease, correlating with specific histologic parameters and identifying cases at higher risk of CKD progression. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD), one of the common microvascular complications of diabetes, is increasing in prevalence worldwide and can lead to End‐stage renal disease. However, there are still gaps in our understanding of the pathophysiology of DKD, and both current clinical diagnostic methods and treatment strategies have drawbacks. According to recent research, long non‐coding RNAs (lncRNAs) are intimately linked to the developmental process of DKD and could be viable targets for clinical diagnostic decisions and therapeutic interventions. Here, we review recent insights gained into lncRNAs in pathological changes of DKD such as mesangial expansion, podocyte injury, renal tubular injury, and interstitial fibrosis. We also discuss the clinical applications of DKD‐associated lncRNAs as diagnostic biomarkers and therapeutic targets, as well as their limitations and challenges, to provide new methods for the prevention, diagnosis, and treatment of DKD. [ABSTRACT FROM AUTHOR]

Macroautophagy/autophagy contributes to maladaptive kidney repair by inducing pro-fibrotic factors such as FGF2 (fibroblast growth factor 2), but the underlying mechanism remains elusive. Here, we show that EGR1 (early growth response 1) was induced in injured proximal tubules after ischemic acute kidney injury (AKI) and this induction was suppressed by autophagy deficiency in inducible, renal tubule-specific atg7 (autophagy related 7) knockout (iRT-atg7 KO) mice. In cultured proximal tubular cells, TGFB1 (transforming growth factor beta 1) induced EGR1 and this induction was also autophagy dependent. Egr1 knockdown in tubular cells reduced FGF2 expression during TGFB1 treatment, leading to less FGF2 secretion and decreased paracrine effects on fibroblasts. ChIP assay detected an increased binding of EGR1 to the Fgf2 gene promoter in TGFB1-treated tubular cells. Both Fgf2 and Egr1 transcription was inhibited by FGF2 neutralizing antibody, suggesting a positive feedback for EGR1-mediated FGF2 autoregulation. This feedback was confirmed using fgf2-deficient tubular cells and fgf2-deficient mice. Upstream of EGR1, autophagy deficiency in mice suppressed MAPK/ERK (mitogen-activated protein kinase) activation in post-ischemic renal tubules. This inhibition correlated with SQSTM1/p62 (sequestosome 1) aggregation and its sequestration of MAPK/ERK. SQSTM1/p62 interacted with MAPK/ERK and blocked its activation during TGFB1 treatment in autophagy-deficient tubular cells. Inhibition of MAPK/ERK suppressed EGR1 and FGF2 expression in maladaptive tubules, leading to the amelioration of renal fibrosis and improvement of renal function. These results suggest that autophagy activates MAPK/ERK in renal tubular cells, which induces EGR1 to transactivate FGF2. FGF2 is then secreted into the interstitium to stimulate fibroblasts for fibrogenesis. Abbreviation: 3-MA: 3-methyladenine; ACTA2/α-SMA: actin alpha 2, smooth muscle, aorta; ACTB/β-actin: actin, beta; AKI: acute kidney injury; aa: amino acid; ATG/Atg: autophagy related; BUN: blood urea nitrogen; ChIP: chromatin immunoprecipitation; CKD: chronic kidney disease; CM: conditioned medium; COL1A1: collagen, type I, alpha 1; COL4A1: collagen, type IV, alpha 1; CQ: chloroquine; DBA: dolichos biflorus agglutinin; EGR1: early growth response 1; ELK1: ELK1, member of ETS oncogene family; FGF2: fibroblast growth factor 2; FN1: fibronectin 1; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HAVCR1/KIM-1: hepatitis A virus cellular receptor 1; IP: immunoprecipitation; LIR: LC3-interacting region; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MAP2K/MEK: mitogen-activated protein kinase kinase; MAPK: mitogen-activated protein kinase; NFKB: nuclear factor kappa B; PB1: Phox and Bem1; PFT: pifithrin α; PPIB/cyclophilin B: peptidylprolyl isomerase B; RT-qPCR: real time-quantitative PCR; SQSTM1/p62: sequestosome 1; TGFB1/TGF-β1: transforming growth factor beta 1; VIM: vimentin [ABSTRACT FROM AUTHOR]

The monocyte–macrophage lineage of inflammatory cells is characterized by significant morphologic and functional plasticity. Macrophages have broad M1 and M2 phenotype subgroups with distinctive functions and dual reno-toxic and reno-protective effects. Macrophages are a major contributor to injury in immune-complex-mediated, as well as pauci-immune, glomerulonephritis. Macrophages are also implicated in tubulointerstitial and vascular disease, though there have not been many human studies. Patrolling monocytes in the intravascular compartment have been reported in auto-immune injury in the renal parenchyma, manifesting as acute kidney injury. Insights into the pathogenetic roles of macrophages in renal disease suggest potentially novel therapeutic and prognostic biomarkers and targeted therapy. This review provides a concise overview of the macrophage-induced pathogenetic mechanism as a background for the latest findings about macrophages' roles in different renal compartments and common renal diseases. [ABSTRACT FROM AUTHOR]

Humans lacking heme oxygenase 1 (HMOX1) display growth retardation, haemolytic anaemia, and vulnerability to stress; however, cardiac function remains unclear. We aimed to explore the cardiac function of zebrafish lacking hmox1a at baseline and in response to stress. We generated zebrafish hmox1a mutants using CRISPR/Cas9 genome editing technology. Deletion of hmox1a increases cardiac output and further induces hypertrophy in adults. Adults lacking hmox1a develop myocardial interstitial fibrosis, restrain cardiomyocyte proliferation and downregulate renal haemoglobin and cardiac antioxidative genes. Larvae lacking hmox1a fail to respond to hypoxia, whereas adults are insensitive to isoproterenol stimulation in the heart, suggesting that hmox1a is necessary for cardiac response to stress. Haplodeficiency of hmox1a stimulates non‐mitochondrial respiration and cardiac cell proliferation, increases cardiac output in larvae in response to hypoxia, and deteriorates cardiac function and structure in adults upon isoproterenol treatment. Intriguingly, haplodeficiency of hmox1a upregulates cardiac hmox1a and hmox1b in response to isoproterenol. Collectively, deletion of hmox1a results in cardiac remodelling and abrogates cardiac response to hypoxia and isoproterenol. Haplodeficiency of hmox1a aggravates cardiac response to the stress, which could be associated with the upregulation of hmox1a and hmox1b. Our data suggests that HMOX1 homeostasis is essential for maintaining cardiac function and promoting cardioprotective effects. [ABSTRACT FROM AUTHOR]

Background 123Iodine‐meta‐iodobenzylguanidine scintigraphy is useful for assessing cardiac autonomic dysfunction and predict outcomes in heart failure (HF). The relationship of cardiac sympathetic function with myocardial remodeling and diffuse fibrosis remains largely unknown. We aimed to evaluate the cardiac sympathetic function of patients with HF and its relation with myocardial remodeling and exercise capacity. Methods and Results Prospectively enrolled patients with HF (New York Heart Association class II–III) were stratified into HF with preserved left ventricular ejection fraction [LVEF] ≥45%) and reduced LVEF. Ventricular morphology/function and myocardial extracellular volume (ECV) fraction were quantified by cardiovascular magnetic resonance, global longitudinal strain by echocardiography, cardiac sympathetic function by heart‐to‐mediastinum ratio from 123iodine‐meta‐iodobenzylguanidine scintigraphy. All participants underwent cardiopulmonary exercise testing. The cohort included 33 patients with HF with preserved LVEF (LVEF, 60±10%; NT‐proBNP [N‐terminal pro‐B‐type natriuretic peptide], 248 [interquartile range, 79–574] pg/dL), 28 with HF with reduced LVEF (LVEF, 30±9%; NT‐proBNP, 743 [interquartile range, 250–2054] pg/dL) and 20 controls (LVEF, 65±5%; NT‐proBNP, 40 [interquartile range, 19–50] pg/dL). Delayed (4 hours) 123iodine‐meta‐iodobenzylguanidine heart‐to‐mediastinum ratio was lower in HF with preserved LVEF (1.59±0.25) and HF with reduced LVEF (1.45±0.16) versus controls (1.92±0.24; P

Introduction: With the increase in number of allografts being performed, the frequency of chronic allograft nephropathy (CAN) has also increased. It is characterized clinically by a progressive decline in glomerular filtration rate, and histologically, by a progressive interstitial fibrosis (IF) and tubular atrophy (TA) which can even be seen in recipients with good allograft function. Objectives: To compare visual analysis with morphometric quantification of interstitial fibrosis and tubular atrophy (IFTA) in renal allograft biopsies and its correlation with renal function. Materials and Methods: A total of 29 renal allograft biopsies were evaluated for fibrosis and tubular atrophy by light microscopy by visual method on Masson’s trichrome‑stained and PAS‑stained sections, respectively, as well as by computer‑assisted morphometry. IFTA was graded as per Banff working classification of renal allograft pathology, which includes a four‑point estimate of the prevalence of IF (ci score) and for tubular atrophy (ct score). The estimation of IF and TA by the two methods was correlated with the renal function state; the serum creatinine level. Result: The percentage of IFTA showed statistically significant correlation between manual and morphometric methods (P < 0.001). Each of the method was correlated with serum creatinine level. IF showed a good correlation with serum creatinine by both the methods; however, no correlation could be established between TA and serum creatinine by either method. Conclusion: When calculating scoring IFTA as per Banff criteria, by either the visual method or the morphometric method, there was a significant correlation between the two methods. However when expressed only as a percentage of total area, the visual method was associated with slight overestimation of both the parameters. [ABSTRACT FROM AUTHOR]

Chronic changes on kidney biopsy specimens include increasing amounts of arteriosclerosis, glomerulosclerosis, interstitial fibrosis and tubular atrophy, enlarged nephron size, and reduced nephron number. These chronic changes are difficult to accurately assess by visual inspection but are reasonably quantified using morphometry. This review describes the various patient populations that have undergone morphometric analysis of kidney biopsies. The common approaches to morphometric analysis are described. The chronic kidney disease outcomes associated with various chronic changes by morphometry are also summarized. Morphometry enriches the characterization of chronicity on a kidney biopsy and this can supplement the pathologist's diagnosis. Artificial intelligence image processing tools are needed to automate the annotations needed for practical morphometric analysis of kidney biopsy specimens in routine clinical care. [ABSTRACT FROM AUTHOR]

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Abstract Background Diabetic nephropathy (DN) is a diabetic complication. LncRNAs are reported to participate in the pathophysiology of DN. Here, the function and mechanism of lncRNA small nucleolar RNA host gene 14 (SNHG14) in DN were explored. Methods Streptozotocin (STZ)‐induced DN mouse models and high glucose (HG)‐treated human mesangial cells (MCs) were used to detect SNHG14 expression. SNHG14 silencing plasmids were applied to examine the function of SNHG14 on proliferation and fibrosis in HG‐treated MCs. Potential targets of SNHG14 were predicted using bioinformatics tools and verified by luciferase reporter, RNA pulldown, and northern blotting assays. The functional role of SNHG14 in DN in vivo was detected by injection with adenoviral vector carrying sh‐SNHG14 into DN mice. Serum creatinine, blood urea nitrogen, blood glucose, 24‐h proteinuria, relative kidney weight, and renal pathological changes were examined in DN mice. Results SNHG14 expression was elevated in the kidneys of DN mice and HG‐treated MCs. SNHG14 silencing inhibited proliferation and fibrosis of HG‐stimulated MCs. SNHG14 bound to miR‐30e‐5p to upregulate SOX4 expression. In rescue assays, SOX4 elevation diminished the effects of SNHG14 silencing in HG‐treated MCs, and SOX4 silencing reversed the effects of SNHG14 overexpression. In in vivo studies, SNHG14 downregulation significantly ameliorated renal injuries and renal interstitial fibrosis in DN mice. Conclusions SNHG14 silencing attenuates kidney injury in DN mice and reduces proliferation and fibrotic phenotype of HG‐stimulated MCs via the miR‐30e‐5p/SOX4 axis.

Purpose. Interstitial fibrosis in papillary thyroid microcarcinoma is a subject which is under-investigated. The aim of this study is to determine the relationship between interstitial fibrosis, the subtypes of papillary microcarcinoma, and the established prognostic factors. Material and Methods. A total of 75 patients diagnosed with papillary microcarcinoma of the thyroid from January 2011 to December 2020 have been evaluated retrospectively, using demographic features, tumor size, subtype of the tumor, surgical margin status, unifocality, lymphovascular invasion, extracapsular spread and lymph node metastasis as parameters. Hematoxylin and eosin slides were reviewed for interstitial fibrosis. Results. The study includes 13 males and 62 females, in a total of 75 patients. There were 51 patients (68%) with interstitial fibrosis and 24 (32%) patients without interstitial fibrosis. Among them, 45 (60%) were classic, 27 (36%) were follicular variant and 3 (4%) were other subtypes. Interstitial fibrosis is significantly associated with bilaterality (p = 0.023), multifocality (p = 0.004), capsule invasion (p < 0.001) and lymph node metastasis (p = 0.043). Evaluation of tumor sub groups showed significant increased risk of lymphovascular invasion in the follicular variant (p = 0.019). Conclusion. Although the relationship of interstitial fibrosis and prognosis of other cancer types has been discussed, there are few studies in the literature regarding its effect on the prognosis of papillary microcarcinoma. Our results show that interstitial fibrosis can be used as a risk factor. However, new studies are needed to clearly reveal the physiopathology of interstitial fibrosis and its effect on tumorigenesis.

Fibrosis is a marker of chronic kidney disease (CKD) and consists of the accumulation of the extracellular matrix (ECM) components, causing the progressive deterioration of kidney function. Human liver stem cells (HLSCs) have anti-fibrotic activity, and HLSC-derived extracellular vesicles (EVs) mediate this effect. Herein, we evaluated the ability of HLSC-EVs to reverse renal and cardiac alterations in a murine model of partial nephrectomy (PNx) that mimics human CKD development. Furthermore, we investigated the contribution of extracellular matrix remodeling-related proteases to the anti-fibrotic effect of HLSC-EVs. PNx was performed by ligation of both poles of the left kidney, followed one week later by the removal of the right kidney. EV treatment started 4 weeks after the nephrectomy, when renal and cardiac alternations were already established, and mice were sacrificed at week eight. HLSC-EV treatment improved renal function and morphology, significantly decreasing interstitial fibrosis, glomerular sclerosis, and capillary rarefaction. This improvement was confirmed by the decreased expression of pro-fibrotic genes. Moreover, EV treatment improved cardiac function and reduced cardiac fibrosis. HLSC-EVs shuttled different proteases with ECM remodeling activity, and matrix metalloproteinase 1 (MMP-1) was involved in their anti-fibrotic effect on renal tissue. HLSC-EV treatment interferes with CKD development and ameliorates cardiomyopathy in PNx mice.

BackgroundPeripheral blood leucocyte telomere length (PBL-TL) is associated with outcomes in patients with idiopathic pulmonary fibrosis. Whether PBL-TL is associated with progression of systemic sclerosis-associated interstitial lung disease (SSc-ILD) is unknown.MethodsA retrospective observational cohort study was performed using prospectively collected data from 213 patients with SSc followed at the University of California San Francisco (UCSF) Scleroderma Center. PBL-TL was measured by quantitative PCR of DNA isolated from peripheral blood. Associations between PBL-TL and pulmonary function test trends in patients with SSc-ILD were assessed by longitudinal analysis using Generalised Linear Mixed Models. Findings were validated in a cohort of 61 patients with SSc-ILD enrolled in the Stanford University Scleroderma Center database.ResultsPatients with UCSF SSc with ILD were found to have shorter PBL-TL compared with those without ILD (6554±671 base pairs (bp) vs 6782±698 bp, p=0.01). Shorter PBL-TL was associated with the presence of ILD (adjusted OR 2.1 per 1000 bp TL decrease, 95% CI [1.25 to 3.70], p=0.006). PBL-TL was shorter in patients with SSc-ILD lacking SSc-specific autoantibodies compared with seropositive subjects (6237±647 bp vs 6651±653 bp, p=0.004). Shorter PBL-TL was associated with increased risk for lung function deterioration with an average of 67 mL greater loss in per year for every 1000 bp decrease in PBL-TL in the combined SSc-ILD cohorts (longitudinal analysis, adjusted model: 95% CI -104 mL to -33 mL, p

Idiopathic pulmonary fibrosis (IPF) and non-IPF, progressive fibrotic interstitial lung diseases (PF-ILD), are associated with a progressive loss of lung function and a poor prognosis. Treatment with antifibrotic agents can slow, but not halt, disease progression, and treatment discontinuation because of adverse events is common. Fibrotic diseases such as these can be mediated by lysophosphatidic acid (LPA), which signals via six LPA receptors (LPA1-6). Signalling via LPA1 appears to be fundamental in the pathogenesis of fibrotic diseases. BMS-986278, a second-generation LPA1 antagonist, is currently in phase 2 development as a therapy for IPF and PF-ILD. This phase 2, randomised, double-blind, placebo-controlled, parallel-group, international trial will include adults with IPF or PF-ILD. The trial will consist of a 42-day screening period, a 26-week placebo-controlled treatment period, an optional 26-week active-treatment extension period, and a 28-day post-treatment follow-up. Patients in both the IPF (n=240) and PF-ILD (n=120) cohorts will be randomised 1:1:1 to receive 30 mg or 60 mg BMS-986278, or placebo, administered orally two times per day for 26 weeks in the placebo-controlled treatment period. The primary endpoint is rate of change in per cent predicted forced vital capacity from baseline to week 26 in the IPF cohort. This study will be conducted in accordance with Good Clinical Practice guidelines, Declaration of Helsinki principles, and local ethical and legal requirements. Results will be reported in a peer-reviewed publication. NCT04308681.

Background Although VCAM‐1 (vascular cell adhesion molecule‐1) and ICAM‐1 (intercellular adhesion molecule‐1) have been associated with incident heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF), the associations of VCAM‐1 and ICAM‐1 with sensitive measures of cardiac structure/function are unclear. The objective of this study is to evaluate associations between VCAM‐1, ICAM‐1, and measures of cardiac structure and function as potential pathways through which cellular adhesion molecules promote HFpEF and AF risk. Methods and Results In MESA (Multi‐Ethnic Study of Atherosclerosis), we evaluated the associations of circulating VCAM‐1 and ICAM‐1 at examination 2 (2002–2004) with measures of cardiac structure/function on cardiac magnetic resonance imaging at examination 5 (2010–2011) after multivariable adjustment. Mediation analysis of left atrial (LA) strain on the association between VCAM‐1 or ICAM‐1 and AF or HFpEF was also performed. Overall, 2304 individuals (63±10 years; 47% men) with VCAM‐1 or ICAM‐1, cardiac magnetic resonance imaging, and covariate data were included in analysis. Higher VCAM‐1 and ICAM‐1 were associated with lower LA peak longitudinal strain and worse global circumferential left ventricular strain but were not associated with left ventricular myocardial scar or interstitial fibrosis. Lower LA peak longitudinal strain mediated 8% (95% CI, 2–30) of the relationship between VCAM‐1 and HFpEF and 9% (95% CI, 2–21) of the relationship between VCAM‐1 and AF. Conclusions Higher VCAM‐1 and ICAM‐1 were associated with lower LA function and left ventricular systolic function but were not associated with myocardial scar or interstitial fibrosis. VCAM‐1 and ICAM‐1 may promote HFpEF and AF risk through impaired LA reservoir function.

Background and aims: Cardiomyocyte hypertrophy and interstitial fibrosis are key components of myocardial remodeling in Heart Failure (HF) with preserved (HFpEF) or reduced ejection fraction (HFrEF). MicroRNAs (miRNAs) are non-coding, evolutionarily conserved RNA molecules that may offer novel insights into myocardial remodeling. This study aimed to characterize miRNA expression in HFpEF (LVEF ≥ 45%) and HFrEF (LVEF

Type XXVIII collagen (COL28) is involved in cancer and lung fibrosis. COL28 polymorphisms and mutations might be involved in kidney fibrosis, but the exact role of COL28 in renal fibrosis is unknown. This study explored the function of COL28 in renal tubular cells by examining the expression of COL28 mRNA and the effects of COL28 overexpression in human tubular cells. COL28 mRNA expression and localization were observed in normal and fibrotic kidney tissues from humans and mice using real-time PCR, western blot, immunofluorescence, and immunohistochemistry. The consequences of COL28 overexpression on cell proliferation, migration, cell polarity, and epithelial-to-mesenchymal transition (EMT) induced by TGF-β1 were examined in human tubular HK-2 cells. COL28 expression was low in human normal renal tissues, mainly observed in the renal tubular epithelial cells and especially in proximal renal tubules. COL28 protein expression in human and mouse obstructive kidney disease was higher than in normal tissues (p < 0.05) and more significant in the UUO2-Week than the UUO1-Week group. The overexpression of COL28 promoted HK-2 cell proliferation and enhanced their migration ability (all p < 0.05). TGF-β1 (10 ng/ml) induced COL28 mRNA expression in HK-2 cells, decreased E-cadherin and increased α-SMA in the COL28-overexpression group compared with controls (p < 0.05). ZO-1 expression decreased while COL6 increased in the COL28-overexpression group compared with controls (p < 0.05). In conclusion, COL28 overexpression promotes the migration and proliferation of renal tubular epithelial cells. The EMT could also be involved. COL28 could be a therapeutic target against renal- fibrotic diseases. [ABSTRACT FROM AUTHOR]

The renal interstitial fibrosis contributes to the progression and deterioration of diabetic nephropathy (DN). Long noncoding RNA taurine-up-regulated gene 1 (TUG1) in kidneys may be down-regulated by hyperglycemia. We aim to explore its role in tubular fibrosis caused by high glucose and the possible target genes of TUG1. In this study, a streptozocin-induced accelerated DN mouse model and a high glucose-stimulated HK-2 cells model was established to evaluate TUG1 expression. Potential targets of TUG1 were analyzed by online tools and confirmed by luciferase assay. A rescue experiment and gene silencing assay were used to investigate whether TUG1 plays its regulation role via miR-145-5p/dual-specificity phosphatase 6 (DUSP6) in HK2 cells. The effects of TUG1 on inflammation and fibrosis in high glucose treated tubular cells were evaluated by in vitro study, as well as in vivo DN mice model through AAV-TUG1 delivery. Results showed TUG1was downregulated in HK2 cells incubated with high glucose while miR-145-5p was upregulated. Overexpression of TUG1 alleviated renal injury by suppressing inflammation and fibrosis in vivo. Overexpression of TUG1 inhibited HK-2 cell fibrosis and relieved the inflammation. A mechanism study demonstrated that TUG1 directly sponged to miR-145-5p, and DUSP6 was identified as a target downstream of miR-145-5p. In addition, miR-145-5 overexpression and DUSP6 inhibition countervailed the impacts of TUG1. Our findings revealed that TUG1 overexpression alleviates kidney injury in DN mice and decreases the inflammatory response and fibrosis of high glucose-stimulated HK-2 cells via miR-145-5p/DUSP6 axis. [ABSTRACT FROM AUTHOR]

In a physiological context, the extracellular matrix (ECM) provides an important scaffold for organs. Dysregulation of ECM in disease conditions, characterised by excess deposition of connective tissue and extracellular matrix in response to a pathological insult, is a key driver of disease progression in multiple organs. The resultant fibrosis is predominantly an irreversible process and directly contributes to, and exacerbates, dysfunction of an affected organ. This is particularly paramount in the kidney, liver, heart and lung. A hybrid Joint Meeting of NC‐IUPHAR and British Pharmacological Society was held in Paris and via a webinar in November 2020, when two successive sessions were devoted to translational advances in fibrosis as a therapeutic target. On the upsurge of response to these sessions, the concept of a special themed issue on this topic emerged, and is entitled Translational Advances in Fibrosis as a Therapeutic Target. In this special issue, we seek to provide an up‐to‐date account of the diverse molecular mechanisms and causal role that fibrosis plays in disease progression (contributing to, and exacerbating, dysfunction of affected organs). Recent developments in the understanding of molecular targets involved in fibrosis, and how their actions can be manipulated therapeutically, are included. LINKED ARTICLES: This article is part of a themed issue on Translational Advances in Fibrosis as a Therapeutic Target. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.22/issuetoc [ABSTRACT FROM AUTHOR]

Objective To observe the therapeutic effect of intragastric administration of empagliflozin on ventricular diastolic dysfunction in hypertensive rats and to explore its possible mechanism. Methods Among 25 male SD rats, 5 underwent abdominal aortic dissection and then the abdominal cavity was closed (sham operation group), the other 20 underwent abdominal aortic coarctation to make hypertensive ventricular diastolic dysfunction models (blood pressure was measured at the 8th weekend after surgery, and echocardiography was performed to detect the ventricular structure and function indexes of rats to evaluate whether the model was successful, and 15 were successfully made). Fifteen hypertensive ventricular diastolic dysfunction model rats were randomly divided into three groups groups A, B, and C (with 5 rats in each), and then underwent echocardiography again (before administration). Rats in the group A were orally administered 10 mg/ (kg. d) of empagliflozin for 4 consecutive weeks (after administration), rats in the group B were treated with normal saline once a day for 4 consecutive weeks, and rats in the group C were not treated. The rats in group A and group B underwent echocardiography immediately after the administration of medication, while the rats in the group C were euthanized and the myocardial tissues were separated. The inflammatory factors, oxidative stress indicators, and collagen fiber indicators in the myocardial tissues of rats in the three groups were detected by ELISA and Western blotting, respectively. Results Compared with the group B, rats of the group A had shorter left ventricular isovolumic relaxation time (IVRT), decreased left ventricular mass (LVM), and decreased left ventricular end systolic diameter (LVIDs) (all P<0. 05). The IVRT of rats in the group A was short, LVM and LVIDs decreased in comparison with those before administration (all P< 0. 05). Compared with the group B, the content of collagen type Ⅰ, collagen type Ⅲ, malondialdehyde (MDA) and transforming growth factor-β (TGF-β) was lower, the content of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) was higher, and the relative expression of NLRP3 was lower in the group A after administration (all P<0. 05). Conclusion Intragastric administration of empagliflozin can alleviate hypertensive ventricular diastolic dysfunction in rats, and the mechanism may be that empagliflozin reduces the expression of MDA, TGF-β, collagen type Ⅰ, collagen type Ⅲ and NLRP3 in myocardial tissues, and promotes the expression of SOD and GSH-PX. [ABSTRACT FROM AUTHOR]

Introduction: With the increase in number of allografts being performed, the frequency of chronic allograft nephropathy (CAN) has also increased. It is characterized clinically by a progressive decline in glomerular filtration rate, and histologically, by a progressive interstitial fibrosis (IF) and tubular atrophy (TA) which can even be seen in recipients with good allograft function. Objectives: To compare visual analysis with morphometric quantification of interstitial fibrosis and tubular atrophy (IFTA) in renal allograft biopsies and its correlation with renal function. Materials and Methods: A total of 29 renal allograft biopsies were evaluated for fibrosis and tubular atrophy by light microscopy by visual method on Masson’s trichrome-stained and PAS-stained sections, respectively, as well as by computer-assisted morphometry. IFTA was graded as per Banff working classification of renal allograft pathology, which includes a four-point estimate of the prevalence of IF (ci score) and for tubular atrophy (ct score). The estimation of IF and TA by the two methods was correlated with the renal function state; the serum creatinine level. Result: The percentage of IFTA showed statistically significant correlation between manual and morphometric methods (P < 0.001). Each of the method was correlated with serum creatinine level. IF showed a good correlation with serum creatinine by both the methods; however, no correlation could be established between TA and serum creatinine by either method. Conclusion: When calculating scoring IFTA as per Banff criteria, by either the visual method or the morphometric method, there was a significant correlation between the two methods. However when expressed only as a percentage of total area, the visual method was associated with slight overestimation of both the parameters.

Abstract Objectives The identification of patients with mitral valve prolapse (MVP) presenting high arrhythmic risk remains challenging. Cardiovascular Magnetic Resonance (CMR) feature tracking (FT) may improve risk stratification. We analyzed the role of CMR-FT parameters in relation to the incidence of complex ventricular arrhythmias (cVA) in patients with MVP and mitral annular disjunction (MAD). Methods 42 patients with MVP and MAD who underwent 1.5 T CMR were classified as MAD-cVA (n = 23, 55%) in case of cVA diagnosed on a 24-h Holter monitoring and as MAD-noVA in the absence of cVA (n = 19, 45%). MAD length, late gadolinium enhancement (LGE), basal segments myocardial extracellular volume (ECV) and CMR-FT were assessed. Results LGE was more frequent in the MAD-cVA group in comparison with the MAD-noVA group (78% vs 42%, p = 0.002) while no difference was observed in terms of basal ECV. Global longitudinal strain (GLS) was reduced in MAD-cVA compared to MAD-noVA (− 18.2% ± 4.6% vs − 25.1% ± 3.1%, p = 0.004) as well as global circumferential strain (GCS) at the mid-ventricular level (− 17.5% ± 4.7% vs − 21.6% ± 3.1%, p = 0.041). Univariate analysis identified as predictors of the incidence of cVA: GCS, circumferential strain (CS) in the basal and mid infero-lateral wall, GLS, regional longitudinal strain (LS) in the basal and mid-ventricular inferolateral wall. Reduced GLS [Odd ratio (OR):1.56 (confidence interval (CI) 95%: 1.45–2.47; p

AbstractThe renal interstitial fibrosis contributes to the progression and deterioration of diabetic nephropathy (DN). Long noncoding RNA taurine-up-regulated gene 1 (TUG1) in kidneys may be down-regulated by hyperglycemia. We aim to explore its role in tubular fibrosis caused by high glucose and the possible target genes of TUG1. In this study, a streptozocin-induced accelerated DN mouse model and a high glucose-stimulated HK-2 cells model was established to evaluate TUG1 expression. Potential targets of TUG1 were analyzed by online tools and confirmed by luciferase assay. A rescue experiment and gene silencing assay were used to investigate whether TUG1 plays its regulation role via miR-145-5p/dual-specificity phosphatase 6 (DUSP6) in HK2 cells. The effects of TUG1 on inflammation and fibrosis in high glucose treated tubular cells were evaluated by in vitro study, as well as in vivo DN mice model through AAV-TUG1 delivery. Results showed TUG1was downregulated in HK2 cells incubated with high glucose while miR-145-5p was upregulated. Overexpression of TUG1 alleviated renal injury by suppressing inflammation and fibrosis in vivo. Overexpression of TUG1 inhibited HK-2 cell fibrosis and relieved the inflammation. A mechanism study demonstrated that TUG1 directly sponged to miR-145-5p, and DUSP6 was identified as a target downstream of miR-145-5p. In addition, miR-145-5 overexpression and DUSP6 inhibition countervailed the impacts of TUG1. Our findings revealed that TUG1 overexpression alleviates kidney injury in DN mice and decreases the inflammatory response and fibrosis of high glucose-stimulated HK-2 cells via miR-145-5p/DUSP6 axis.

AbstractType XXVIII collagen (COL28) is involved in cancer and lung fibrosis. COL28 polymorphisms and mutations might be involved in kidney fibrosis, but the exact role of COL28 in renal fibrosis is unknown. This study explored the function of COL28 in renal tubular cells by examining the expression of COL28 mRNA and the effects of COL28 overexpression in human tubular cells. COL28 mRNA expression and localization were observed in normal and fibrotic kidney tissues from humans and mice using real-time PCR, western blot, immunofluorescence, and immunohistochemistry. The consequences of COL28 overexpression on cell proliferation, migration, cell polarity, and epithelial-to-mesenchymal transition (EMT) induced by TGF-β1 were examined in human tubular HK-2 cells. COL28 expression was low in human normal renal tissues, mainly observed in the renal tubular epithelial cells and especially in proximal renal tubules. COL28 protein expression in human and mouse obstructive kidney disease was higher than in normal tissues (p

During diabetic kidney disease (DKD), ectopic ceramide (CER) accumulation in renal tubular epithelial cells (RTECs) is associated with interstitial fibrosis and albuminuria. As RTECs are primarily responsible for renal energy metabolism, their function is intimately linked to mitochondrial quality control. The role of CER synthesis in the progression of diabetic renal fibrosis has not been thoroughly investigated. In this study, we observed a significant upregulation of ceramide synthase 6 (Cers6) expression in the renal cortex of db/db mice, coinciding with increased production of CER (d18:1/14:0) and CER (d18:1/16:0) by Cer6. Concurrently, the number of damaged mitochondria in RTECs rose. Cers6 deficiency reduced the abnormal accumulation of CER (d18:1/14:0) and CER (d18:1/16:0) in the kidney cortex, restoring the PTEN-induced kinase 1 (PINK1)-mediated mitophagy in RTECs, and resulting in a decrease in damaged mitochondria and attenuation of interstitial fibrosis in DKD. Automated docking analysis suggested that both CER (d18:1/14:0) and CER (d18:1/ 16:0) could bind to the PINK1 protein. Furthermore, inhibiting PINK1 expression in CERS6 knockdown HK-2 cells diminished the therapeutic effect of CERS6 deficiency on DKD. In summary, CERS6-derived CER (d18:1/14:0) and CER (d18:1/16:0) inhibit PINK1-regulated mitophagy by possibly binding to the PINK1 protein, thereby exacerbating the progression of renal interstitial fibrosis in DKD. NEW & NOTEWORTHY This article addresses the roles of ceramide synthase 6 (CERS6) and CERS6-derived ceramides in renal tubular epithelial cells of diabetic kidney disease (DKD) associated interstitial fibrosis. Results from knockdown of CERS6 adjusted the ceramide pool in kidney cortex and markedly protected from diabetic-induced kidney fibrosis in vivo and in vitro. Mechanically, CERS6-derived ceramides might interact with PINK1 to inhibit PINK1/Parkin-mediated mitophagy and aggravate renal interstitial fibrosis in DKD. [ABSTRACT FROM AUTHOR]

Background: Mycobacterium avium complex (MAC) causes chronic respiratory infectious diseases with diverse clinical features and prognoses. Pleuroparenchymal fibroelastosis (PPFE) is a rare disease characterised by pleural fibrosis with subjacent intra-alveolar fibrosis and alveolar septal elastosis, with unique chest high-resolution CT (HRCT) features (radiological PPFE). An association between recurrent respiratory infections and PPFE formation has been hypothesised; however, the clinical significance of PPFE in MAC lung disease remains unclear.Methods: This retrospective, multicentre study investigated the prevalence of radiological PPFE in patients with MAC lung disease and its association with clinical features and outcomes. Radiological PPFE was diagnosed on the basis of HRCT findings. Prognostic factors were identified using Cox proportional hazards and Fine-Gray models.Results: Of 850 consecutive patients with definite MAC lung disease, 101 (11.9%) exhibited radiological PPFE. Patients with radiological PPFE had unique characteristics, such as lower body mass index, lower survival rate (5-year cumulative survival rate, 63.1% vs 91.7%; p<0.001) and a higher incidence of respiratory-related death (5-year cumulative incidence, 31.1% vs 3.6%; p<0.001), than those without radiological PPFE. In the multivariable analysis, the presence of radiological PPFE was independently associated with all-cause mortality (adjusted HR, 4.78; 95% CI, 2.87 to 7.95; p<0.001) and respiratory-related death (adjusted HR, 3.88; 95% CI, 2.14 to 7.01; p<0.001).Interpretation: This large-scale study demonstrated that in patients with MAC lung disease, radiological PPFE was common, a phenotype associated with unique clinical features and poor prognosis, particularly respiratory-related death. The specific management of this subgroup should be established. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is characterized by increased interstitial fibrosis and tubular atrophy (IFTA) in the kidney. Chronic hematuria is a hallmark of several human kidney diseases and often is seen in patients on anticoagulation therapy. We had previously demonstrated that chronic hematuria associated with warfarin increases IFTA in 5/6 nephrectomy (5/6NE) rats, and such treatment increases reactive oxygen species (ROS) in the kidney. The goal of this study was to evaluate the effects of the antioxidant N‐acetylcysteine (NAC) on the progression of IFTA in 5/6NE mice. 5/6NE C57BL/6 and 5/6NE 129S1/SvImJ mice were treated with warfarin alone or with warfarin and NAC for 23 weeks. Serum creatinine (SCr), hematuria, blood pressure (BP), and ROSs in the kidney were measured; kidney morphology was evaluated. Warfarin doses were titrated to achieve prothrombin time (PT) increase to the levels seen with therapeutic human doses. Warfarin treatment resulted in an increased SCr, systolic BP, hematuria, expression of TGF‐ß and ROS in the kidney in both mouse strains. Tumor necrosis factor alpha (TNF‐ɑ) levels in the serum were increased in 5/6NE mice treated with warfarin. IFTA was increased as compared with control 5/6NE mice, and this increase in IFTA was more prominent in 129S1/SvImJ than in C57BL/6 mice. NAC ameliorated the warfarin‐associated increase in SCr and BP but not hematuria. IFTA, TGF‐ß, and ROS in the kidney as well as TNF‐ɑ levels in the serum were reduced in mice treated with NAC and warfarin as compared to mice treated with warfarin alone. NAC mitigates the increase in SCr and IFTA in mice with chronic hematuria by reducing oxidative stress in the kidney. This data open novel possibilities for treatments in CKD patients. [ABSTRACT FROM AUTHOR]

We present a 41‐year‐old man with idiopathic interstitial pneumonia and pulmonary hypertension (PH) in the setting of a non‐autoimmune background whose clinical presentation masqueraded pulmonary veno‐occlusive disease (PVOD). Because of no histological evidence of venous occlusion in his previous lung biopsy, phosphodiesterase type‐5 inhibitor was given, resulting in sudden onset of pulmonary edema. At autopsy, there were histological features of interstitial fibrosis with occlusion of the lobular septal veins and venules. Clinical presentations of PH due to interstitial fibrosis with pulmonary venous lesions may simulate those of PVOD and careful diagnostic and therapeutic approaches are required. [ABSTRACT FROM AUTHOR]