Podocyte-specific YAP activation triggers crescentic glomerulonephritis through cross-talk with parietal epithelial cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE272779 | GEO | 2025/05/26
REPOSITORIES: GEO
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Project description:Podocyte-specific YAP activation triggers crescentic glomerulonephritis through cross-talk with parietal epithelial cells
| PRJNA1138722 | ENA
Project description:Crescentic rapidly progressive glomerulonephritis (RPGN) represents the most aggressive form of acquired glomerular disease. While most therapeutic approaches involve potentially toxic immunosuppressive strategies, the pathophysiology remains incompletely understood. Podocytes are glomerular epithelial cells that are normally growth-arrested because of the expression of cyclin-dependent kinase (CDK) inhibitors. An exception is in RPGN where podocytes undergo a deregulation of their differentiated phenotype and proliferate. Here we demonstrate that microRNA-92a (miR-92a) is enriched in podocytes of patients and mice with RPGN. The CDK inhibitor p57Kip2 is a major target of miR-92a that constitutively safeguards podocyte cell cycle quiescence. Podocyte-specific deletion of miR-92a in mice de-repressed the expression of p57Kip2 and prevented glomerular injury in RPGN. Administration of an anti-miR-92a after disease initiation prevented albuminuria and kidney failure, indicating miR-92a inhibition as a potential therapeutic strategy for RPGN. We demonstrate that miRNA induction in epithelial cells can break glomerular tolerance to immune injury.
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Project description:Glomerulonephritis following an enterococcal endocarditis is an extremely rare and life-threatening condition. We present the case of a 71-year-old patient with rapidly progressive glomerulonephritis following enterococcal endocarditis after surgical replacement of the aortic valve. The combination of antibiotic therapy, corticosteroid therapy and haemodialysis led to an improvement in renal function; however, the severity of cardiac deterioration resulted in a fatal outcome.
| S-EPMC10455847 | biostudies-literature
Project description:The second messenger cyclic AMP (cAMP) is involved in many aspects of renal physiology and disease. Epac is an effector of cAMP and its pathophysiological role in the development of chronic kidney diseases (CKD) has yet to be determined. Here, we show that total Epac1 isoform genetic deletion does not cause any baseline renal abnormalities but remarkably potentiates the deterioration of renal structure and function during the progression of the nephrotoxic serum (NTS)-induced glomerular nephritis (GN). Similarly, podocyte Epac1 deletion in podocytes exacerbated GN development. Global gene expression profile in mouse glomeruli using RNAseq analysis indicates a transcriptomic signature of GN related to immune system, extracellular matrix, and cytoskeleton gene dysregulation at the onset of the disease. Furthermore, glomeruli with podocyte Epac1 deletion display altered mitochondrion and metabolic processes in nephritic mice. Consistently, mechanistic analysis demonstrates that Epac1 activation increases human podocyte mitochondrial function to cope with extra energy demand in stress condition. Of particular importance, Epac1 increases aerobic glycolysis to ameliorate podocyte viability and motility. Therefore, the metabolic flexibility mediated by Epac1 constitutes a protective mechanism against podocyte injury. Altogether these data highlight the potential of Epac1 as a therapeutic approach for CKD treatment.
2024-06-10 | GSE237097 | GEO
Project description:Background: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by multiple organ involvement. Lupus nephritis (LN) is a common manifestation with a wide variety of histological appearances. Matrix metalloproteinases (MMP) 2 and 9 are gelatinases capable of degrading glomerular basement membrane type IV collagen, which have been associated with LN. We examine the expression of MMP2 and MMP9 in different classes of LN. Methods: MMP2 and MMP9 expression was detected by immunohistochemistry in sections from renal biopsy specimens with class III, class IV and class V LN (total n = 31), crescentic immunoglobulin A nephropathy (n = 6), pauci-immune glomerulonephritis (n = 7), minimal change disease (n = 2), mesangiocapillary glomerulonephritis (n = 7), diabetic nephropathy (n = 12) and histologically normal controls (n = 8). Results: MMP2 and MMP9 were not expressed in all classes of LN, but were observed in LN with cellular and fibrocellular crescents. MMP2/MMP9 was expressed in cellular and fibrocellular crescents regardless of glomerulonephritis but not observed in inactive fibrous crescents or with mesangial proliferation. This suggests that MMP2 and MMP9 are involved in the development of extracapillary proliferative lesions. Conclusions: MMP2/MMP9 is expressed with active extracapillary proliferation. Further study is necessary to define whether the expression of MMP2/MMP9 reflects a role in glomerular repair after injury, a role in organ-level immune responses or a role as a marker of epithelialization.
| S-EPMC5455255 | biostudies-literature
Project description: Not available
| S-EPMC6551570 | biostudies-literature
Project description:A 46-year-old female presented with a chief complaint of fatigue and intermittent painless gross hematuria for one month. The patient was fluid overloaded on physical examination and noted to be in acute renal failure with a serum creatinine of 10.8 mg/dL. The patient was emergently started on hemodialysis. Serologies were negative for antinuclear antibody (ANA), anti-neutrophilic cytoplasmic antibody (ANCA), and anti-glomerular basement membrane (anti-GBM) antibody. However, renal biopsy revealed 90% glomerular involvement by temporally heterogeneous crescents ranging from cellular to fibrous. Immunofluorescence studies revealed strong, linear glomerular capillary wall staining for immunoglobulin G (IgG). Although the patient was treated with pulse dose steroids and cyclophosphamide, the patient ultimately developed infectious complications from immunosuppression, and treatment was terminated. This case highlights the atypical presentation of anti-GBM disease diagnosed based on renal biopsy with negative serologies. Although rare, the possibility of atypical anti-GBM antibodies which are not detected by standard commercial assays should be considered in such cases.
| S-EPMC6603348 | biostudies-literature
Project description:IntroductionCrescentic glomerulonephritis (CrGN) is a histologic feature of severe glomerular injury, clinically characterized by a rapid decline of renal function when not treated in a timely fashion. Factors associated with CrGN prognosis have not been thoroughly investigated. This study investigated the prognostic predictors of renal outcomes associated with CrGN, such as the histopathologic classification of anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis, arteriosclerosis, and tertiary lymphoid organ (TLO) formation.MethodsA total of 114 patients diagnosed with CrGN between 2010 and 2018 at two university-based hospitals has been retrospectively analyzed. Relationships between potential predictors and renal outcomes were analyzed using Cox proportional hazards model and linear regression analysis.ResultsThe mean age was 61.0 ± 15.3 years, and 49.1% were male. Among them, 92 (80.7%) and 11 (9.6%) patients were positive for ANCA and for anti-glomerular basement membrane antibody, respectively. During the median follow-up of 458.0 days, 55 patients (48.2%) had advanced to end-stage renal disease (ESRD). Cox proportional hazards analysis revealed that patients under the mixed and sclerotic classes had worse renal survival compared to those in the focal class (mixed: hazard ratio [HR], 3.74; 95% confidence interval [CI], 1.18 to 11.82; P = 0.025; sclerotic: HR, 4.84; 95% CI, 1.44 to 16.32; P = 0.011). Severe arteriosclerosis was also associated with poor renal survival (HR, 2.44; 95% CI, 1.04 to 5.77; P = 0.042). TLOs were observed in 41 patients (36.0%). Moreover, TLO formation was also a prognostic factor for ESRD (HR, 1.82; 95% CI, 1.03 to 3.21; P = 0.040). In the multivariate linear regression analysis, age and sclerotic class were independent predictors for the change in estimated glomerular filtration rate during 1 year after biopsy.ConclusionsSpecific histopathologic findings, histopathologic classification, severity of arteriosclerosis, and TLO formation provide helpful information in predicting renal outcomes associated with CrGN.
| S-EPMC7384637 | biostudies-literature
Project description:Non-resolving inflammation plays a critical role during the transition from renal injury towards end-stage renal disease. The glucocorticoid-inducible protein annexin A1 has been shown to function as key regulator in the resolution phase of inflammation, but its role in immune-mediated crescentic glomerulonephritis has not been studied so far. Methods: Acute crescentic glomerulonephritis was induced in annexin A1-deficient and wildtype mice using a sheep serum against rat glomerular basement membrane constituents. Animals were sacrificed at d5 and d10 after nephritis induction. Renal leukocyte abundance was studied by immunofluorescence and flow cytometry. Alterations in gene expression were determined by RNA-Seq and gene ontology analysis. Renal levels of eicosanoids and related lipid products were measured using lipid mass spectrometry. Results: Histological analysis revealed an increased number of sclerotic glomeruli and aggravated tubulointerstitial damage in the kidneys of annexin A1-deficient mice compared to the wildtype controls. Flow cytometry analysis confirmed an increased number of CD45+ leukocytes and neutrophil granulocytes in the absence of annexin A1. Lipid mass spectrometry showed elevated levels of prostaglandins PGE2 and PGD2 and reduced levels of antiinflammatory epoxydocosapentaenoic acid regioisomers. RNA-Seq with subsequent gene ontology analysis revealed induction of gene products related to leukocyte activation and chemotaxis as well as regulation of cytokine production and secretion. Conclusion: Intrinsic annexin A1 reduces proinflammatory signals and infiltration of neutrophil granulocytes and thereby protects the kidney during crescentic glomerulonephritis. The annexin A1 signaling cascade may therefore provide novel targets for the treatment of inflammatory kidney disease.
| S-EPMC9605209 | biostudies-literature
Project description: Not available
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