Alport syndrome in Romani in the Czech Republic
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ABSTRACT:
PROVIDER: PRJEB58716 | ENA |
REPOSITORIES: ENA
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Project description:Modulation of miRNA expression in glomerular cells is associated with renal disease. Here, we investigated the role of miR-93-5p in mitigating glomerular damage in Alport syndrome and whether the disease-modifying activity of extracellular vesicles from human amniotic fluid stem cells (hAFSC-EVs) is mediated by their miR-93-5p-specific cargo. We identified downregulation of miR-93-5p specifically in glomerular endothelial cells in Alport syndrome along disease progression. Silencing of miR-93-5p in hAFSC-EVs changed the transcriptomic and proteomic profile, regulating EV disease-modifying activity. Compared to naive hAFSC-EVs, silenced hAFSC-EVs did not rescue glomerular endothelial function in vitro and did not restore kidney function in vivo. We established that hAFSC-EVs regulate VEGFR1 and VEGFR2 signaling by miR-93-5p cargo transfer, highlighting that miR-93-5p can restore glomerular endothelial cell biology. Spatial Transcriptomics analysis of hAFSC-EVs injected kidneys showed that EVs can reverse pathways altered during disease progression by stimulating pro-regenerative processes, specifically in the glomerulus, by regulating miR-93-5p targets. Alteration of glomerular endothelial cell transcriptomics and miR-93-5p targets was also confirmed in biopsies of human Alport patients using Spatial Molecular Imaging. We demonstrated the critical role of miR-93-5p in glomerular endothelial cells and the capability of hAFSC-EVs to regulate miR-93-5p and its targets in Alport syndrome.
2026-02-11 | GSE318476 | GEO
Project description:Alport syndrome (AS) is a rare disease characterized by defective glomerular basement membranes, caused by mutations in COL4A3, COL4A4 and COL4A5, which synthesize collagen type IV. Patients present with progressive proteinuria, hematuria and podocyte loss. There is currently no cure for AS, and this is mainly due to its complex and variable pathogenesis, as well as the lack of models that can faithfully mimic the human phenotype.
2023-02-21 | PXD039214 | Pride
Project description:Alport syndrome is a glomerular disease. To understand the disease progression of alport syndrome and potential therapeutical effects of hEV derived from AFSCs, we performed spatial transcriptomics to profile the heterogeniety of cell populations in kidneys of mouse of AS through disease progression and hEV treated AS mice as well. Our analysis sheds light on key functional parts of the kidney responsible in disease progression as well as potential targets of hEV therapy.
2024-11-30 | GSE245039 | GEO
Project description:SPARC Upregulation Mediates Podocyte Injury in Alport Syndrome Mice
| PRJNA1336160 | ENA
Project description:In study we investigated podocyte maturation, with a particular focus on type IV collagen maturation in the glomerular basement membrane (GBM) of kidney organoids over extended culture periods (comparing Control Organoid d22 R2 with Control Organoid d38). The secondary aim was to compare the gene expression profiles of podocytes in X-linked Alport syndrome (XLAS) organoid models with isogenic controls at an early culture time point (day 22). Two distinct batches of sample collection were conducted to capture early and later stages of GBM development. In the first batch, three libraries were generated by collecting 16 organoids from one isogenic control, one severe XLAS model, and one moderate XLAS model on day 22 of differentiation. In the second batch, two libraries were created to evaluate the impact of culture duration on GBM maturation by harvesting an additional isogenic control organoid at both day 22 and day 38 of culture. Organoids were dissociated using a two-step enzymatic and mechanical protocol to obtain single-cell suspensions, with cell viability ranging between 70% and 85%. This experimental design enabled a comparative analysis of GBM maturation dynamics between early and late time points and across different severities of XLAS. Findings from this study provided insights into the cellular mechanisms underlying GBM abnormalities in Alport syndrome and supported the potential for GBM maturation in kidney organoids over time.
2025-07-29 | GSE281081 | GEO
Project description:RNAseq of mouse kidney RNA from Col4a5 muntant mice crossed with diversity ourbred mice to find modifier genes of Alport disease.
2020-03-10 | GSE146660 | GEO
Project description:Background: Renal lipid dysmetabolism contributes to glomerular disease progression, including Alport Syndrome. We recently identified alterations in the apolipoprotein M/sphingosine-1-phosphate/sphingosine-1-phosphate receptor 4 signaling axis in glomeruli from patients with glomerular disease. Methods: We utilized Col4a3 knockout mice and immortalized podocytes derived from these mice as a mouse model of Alport Syndrome. Mice and podocytes were treated with recombinant apolipoprotein M or the sphingosine-1-phosphate receptor 4 antagonist, CYM50358. Results: Col4a3-/- glomeruli and podocytes exhibited reduced apolipoprotein M and increased sphingosine-1-phosphate receptor 4 expression and increased sphignsoine-1-phosphate levels, mirroring findings in patients with glomerular disease. Treatment with apolipoprotein M or CYM50358 reduced albuminuria, BUN, and plasma creatinine, and ameliorated glomerulosclerosis, tubulointerstitial fibrosis, podocyte loss and foot process effacement. Both treatments reduced triglyceride and cholesterol accumulation in glomeruli and podocytes. RNA-seq analysis of Col4a3-/- revealed that sphingosine-1-phosphate receptor 4 antagonism upregulated lysosomal and autophagy-related genes. Western blot analysis confirmed increased LC3-II/LC3-I ratios and decreased p62, indicating enhanced autophagic flux. Treated podocytes showed increased lysosome numbers and co-localization with lipid droplets. In contrast, apolipoprotein M had no effect on autophagy but promoted cholesterol efflux. Conclusions: The apolipoprotein M/sphingosine-1-phosphate axis is dysregulated in Col4a3-/- podocytes. Targeting this pathway through apolipoprotein M supplementation or sphingosine-1-phosphate receptor 4 antagonism improves renal function and reduces lipid accumulation by enhancing either cholesterol efflux or autophagy, respectively. These findings suggest that restoring lipid homeostasis via targeting the APOM/S1P/S1PR4 axis may be a promising therapeutic strategy for Alport Syndrome and other glomerular diseases.
2025-06-20 | GSE300237 | GEO
Project description:Alport syndrome (AS) is a hereditary kidney disease with no curative treatment, which characterized by hematuria, proteinuria, and progressive kidney failure. Podocyte injury has been observed in AS, whereases, the mechanism is still unclear. Reported studies showed the expression level of secreted protein acidic and rich in cysteine (SPARC) correlated with podocyte injury in chronic kidney diseases, yet its mechanism still unknown. Especially, its role in AS-related podocyte injury is unclear. Therefore, the kidney of Col4a3-/- AS mice was used to detect SPARC expression, location, and podocyte injury, and mouse podocyte cell line (MPC5) was used to explore the mechanism of SPARC-induced podocyte injury. Besides, SPARC expression in both urine and kidney samples from AS patients were analyzed. The results showed, SPARC upregulated and located in podocytes were detected in Col4a3-/- AS mice, and increased inflammatory cytokines, impaired podocyte structure and function were identified in SPARC-overexpression MPC5, importantly, knockdown adhesion G protein-coupled receptor B1 (ADGRB1) exerted a protective effect. In AS patients, urinary increased level of SPARC was detected, SPARC deposition in glomeruli of kidney sections was identified. Our findings identified SPARC as a key mediator of podocyte injury in AS, with ADGRB1 acting as its downstream effector.
2025-10-04 | GSE309489 | GEO
Project description:Alport syndrome (AS) is a hereditary glomerulonephritis caused by COL4A3, COL4A4 or COL4A5 gene mutations and characterized by abnormalities of glomerular basement membranes (GBMs). Due to a lack of curative treatments, the condition proceeds to end-stage renal disease even in adolescents. Hampering drug discovery is the absence of effective in vitro methods for testing the restoration of normal GBMs. Here, we aimed to develop kidney organoid models from AS patient iPSCs for this purpose. We established iPSC-derived collagen α5(IV)-expressing kidney organoids and confirmed that kidney organoids from COL4A5 mutation-corrected iPSCs restore collagen α5(IV) protein expression. Importantly, our model recapitulates the differences in collagen composition between iPSC-derived kidney organoids from mild and severe AS cases. Furthermore, we demonstrate that a chemical chaperone, 4-phenyl butyric acid, has the potential to correct GBM abnormalities in kidney organoids showing mild AS phenotypes. This iPSC-derived kidney organoid model will contribute to drug discovery for AS.
2023-07-06 | GSE236314 | GEO