Disruption of the exocyst induces podocyte loss and dysfunction
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA525148 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8655510_1.fastq.gz | Fastqsanger.gz | |||
| SRR8655510_2.fastq.gz | Fastqsanger.gz | |||
| SRR8655511_1.fastq.gz | Fastqsanger.gz | |||
| SRR8655511_2.fastq.gz | Fastqsanger.gz | |||
| SRR8655512_1.fastq.gz | Fastqsanger.gz |
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Project description:Although the slit diaphragm proteins in podocytes are uniquely organized to maintain glomerular filtration assembly and function, little is known about the underlying mechanisms that participate in trafficking these proteins to the correct location for development and homeostasis. Identifying these mechanisms will likely provide novel targets for therapeutic intervention to preserve podocyte function following glomerular injury. Analysis of structural variation in cases of human nephrotic syndrome identified rare heterozygous deletions of EXOC4 in two patients. This suggested that disruption of the highly-conserved eight-protein exocyst trafficking complex could have a role in podocyte dysfunction. Indeed, mRNA profiling of injured podocytes identified significant exocyst down-regulation. To test the hypothesis that the exocyst is centrally involved in podocyte development/function, we generated homozygous podocyte-specific Exoc5 (a central exocyst component that interacts with Exoc4) knockout mice that showed massive proteinuria and died within 4 weeks of birth. Histological and ultrastructural analysis of these mice showed severe glomerular defects with increased fibrosis, proteinaceous casts, effaced podocytes, and loss of the slit diaphragm. Immunofluorescence analysis revealed that Neph1 and Nephrin, major slit diaphragm constituents, were mislocalized and/or lost. mRNA profiling of Exoc5 knockdown podocytes showed that vesicular trafficking was the most affected cellular event. Mapping of signaling pathways and Western blot analysis revealed significant up-regulation of the mitogen-activated protein kinase and transforming growth factor-β pathways in Exoc5 knockdown podocytes and in the glomeruli of podocyte-specific Exoc5 KO mice. Based on these data, we propose that exocyst-based mechanisms regulate Neph1 and Nephrin signaling and trafficking, and thus podocyte development and function.
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Project description:In this study we plan to compare the profiles of control sample (cultured podocytes) with the Exoc5 knock down in cutured podocytes to examine the differentially expressed genes.
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Project description:The progression of proteinuric kidney disease is associated with podocyte loss but the mechanisms remain unclear. Podocytes reenter the cell cycle to repair damaged ds DNA breaks. However, unsuccessful repair results in podocytes crossing the G1/S checkpoint and undergoes abortive cytokinesis. In this study, we identified Pfn1 as a major contributor in maintaining glomerular integrity and its loss in mice results in severe proteinuria, and kidney failure due to podocyte mitotic catastrophe, characterized by abundant multinucleated cells. Reentry of podocytes were identified by using FUCCI-2aR mice, accompanying the alteration of cell-cycle associated proteins, such as P21, P53, Cyclin B, and Cyclin D. Podocyte-specific translating ribosome affinity purification (TRAP) and RNAseq revealed a reduction of Ribosomal RNA-processing protein 8 (Rrp8) and re-expression of Rrp8 partially rescued the in-vitro phenotype. Clinical analysis of patients with proteinuric kidney disease demonstrated multinucleated podocytes and reduced podocyte profilin1 in kidney tissue. These results suggest that profilin is indispensible in regulating podocyte cell cycle and its disruption contributes to podocyte loss through mitotic catastrophe.
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Project description:Background. Ageing is one of the main risk factors of cardiovascular disease. Pericytes are capillary-associated mural cells involved in the maintenance and stability of the vascular network. In the heart, the consequences of ageing on cardiac pericytes are unknown. Methods. In this study, we have combined single nucleus RNA sequencing and histological analysis to determine the effects of ageing on cardiac pericytes. Furthermore, we have conducted in vivo and in vitro analysis of RGS5 loss of function and finally have perfomed pericytes-fibroblasts co-culture studies to understand the effect of RGS5 loss of function in pericytes on the neighbouring fibroblasts. Results. We showed that ageing reduces the pericyte area and coverage. Single nucleus RNA sequencing analysis further revealed that the expression of the Regulator of G protein signalling 5 (Rgs5) is reduced in old cardiac pericytes. In vivo and in vitro studies showed that the deletion of RGS5 induces morphological changes and a pro-fibrotic gene expression signature characterized by the expression of different extracellular matrix components and growth factors like TGFB2 and PDGFB in pericytes. Indeed, the culture of fibroblasts with the supernatant of RGS5 deficient pericytes induced their activation characterized by the increased expression of α smooth muscle actin in a TFGβ2 dependent mechanism. Conclusions. Our results identify RGS5 as a crucial regulator of pericyte function during cardiac ageing. The deletion of RGS5 causes cardiac dysfunction and induces myocardial fibrosis, one of the hallmarks of cardiac ageing.
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Project description:Current therapies for Fabry disease are based on reversing intra-cellular accumulation of globotriaosylceramide (Gb3) by enzyme replacement (ERT) or chaperone mediated stabilization, thereby alleviating lysosome dysfunction. However, the therapeutic effect in the regression of end-organ damage (ie. kidney damage) is limited. Ultrastructural analysis of serial human kidney biopsies showed that long-term use of ERT reduced Gb3 accumulation in podocytes but did not alter podocyte injury. A novel CRISPR-/CAS9-mediated -Galactosidase knockout podocyte cell line confirmed ERT-mediated reversal of Gb3 accumulation without resolution of lysosomal dysfunction. Transcriptomic-based connectivity mapping and SILAC-based quantitative proteomics identified alpha-synuclein (SNCA) accumulation as a key event mediating podocyte injury.
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Project description:Background. Ageing is one of the main risk factors of cardiovascular disease. Pericytes are capillary-associated mural cells involved in the maintenance and stability of the vascular network. In the heart, the consequences of ageing on cardiac pericytes are unknown. Methods. In this study, we have combined single nucleus RNA sequencing and histological analysis to determine the effects of ageing on cardiac pericytes. Furthermore, we have conducted in vivo and in vitro analysis of RGS5 loss of function and finally have perfomed pericytes-fibroblasts co-culture studies to understand the effect of RGS5 loss of function in pericytes on the neighbouring fibroblasts. Results. We showed that ageing reduces the pericyte area and coverage. Single nucleus RNA sequencing analysis further revealed that the expression of the Regulator of G protein signalling 5 (Rgs5) is reduced in old cardiac pericytes. In vivo and in vitro studies showed that the deletion of RGS5 induces morphological changes and a pro-fibrotic gene expression signature characterized by the expression of different extracellular matrix components and growth factors like TGFB2 and PDGFB in pericytes. Indeed, the culture of fibroblasts with the supernatant of RGS5 deficient pericytes induced their activation characterized by the increased expression of α smooth muscle actin in a TFGβ2 dependent mechanism. Conclusions. Our results identify RGS5 as a crucial regulator of pericyte function during cardiac ageing. The deletion of RGS5 causes cardiac dysfunction and induces myocardial fibrosis, one of the hallmarks of cardiac ageing.
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Project description:Deceased kidney donation after brain death (DBD) is the main source of transplants, yet these grafts yield inferior transplant outcomes when compared to living donation. In brain death, cerebral injury contributes to systemic biological dysregulation, causing significant cellular stress in donor kidneys that adversely impacts the quality of grafts. Here, we hypothesized that proteolytic processes in DBD kidneys might lead to podocyte damage with subsequent development of post-transplant dysfunction. Using protein topography and migration analysis platform (PROTOMAP), we mapped degradation profiles of cytoskeletal proteins in DBD kidneys. Cytoskeletal proteolytic degradation was further studied by Immunoblotting on a separate cohort of deceased and living donor kidney biopsies. To investigate potential mechanism of kidney cytoskeletal protein degradation, in-vitro human podocytes and ex-vivo precision-cut human kidney slices were employed. We found novel proteolytic profiles of key podocyte cytoskeletal proteins in donor kidneys associated with suboptimal posttransplant function. These were unique to brain-death and were not observed in circulatory-death or living-donor kidneys. Talin-specific protein degradation in DBD kidneys indicated Calpain-1 activation may have a key role in proteolytic processes observed in the dysfunctional kidneys. Investigation of the underlying mechanism suggests that Transforming-Growth Factor-β (TGFβ) induces Calpain-1 activation, leading to brain-death specific podocyte degradation patterns and dysregulation of actin cytoskeleton; events that were prevented, in-vitro, by Calpain inhibition. Conclusion Our data demonstrate that podocyte protein degradation impacts the quality of DBD kidneys, propose a role of TGFβ mediated Calpain-1 proteolytic processing of cytoskeletal Talin-1, suggesting therapeutic opportunities to prevent kidney dysfunction.
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