Single cell transcriptomics reveal disrupted kidney filter cell-cell interactions after early and selective podocyte injury
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE174102 | GEO | 2021/05/09
REPOSITORIES: GEO
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Project description:Podocyte injury is involved in the onset and progression of various kidney diseases. We previously demonstrated that the transcription factor, old astrocyte specifically induced substance (OASIS) in myofibroblasts, contributes to kidney fibrosis, as a novel role of OASIS in the kidneys. Importantly, we found that OASIS is also expressed in podocytes; however, the pathophysiological significance of OASIS in podocytes remains unknown. Upon lipopolysaccharide (LPS) treatment, there is an increase in OASIS in murine podocytes. Enhanced serum creatinine levels and tubular injury, but not albuminuria and podocyte injury, are attenuated upon podocyte-restricted OASIS knockout in LPS-treated mice, as well as diabetic mice. The protective effects of podocyte-specific OASIS deficiency on tubular injury are mediated by protein kinase C iota (PRKCI/PKCι), which is negatively regulated by OASIS in podocytes. Furthermore, podocyte-restricted OASIS transgenic mice show tubular injury and tubulointerstitial fibrosis, with severe albuminuria and podocyte degeneration. Finally, there is an increase in OASIS-positive podocytes in the glomeruli of patients with minimal change nephrotic syndrome and diabetic nephropathy. Taken together, OASIS in podocytes contributes to podocyte and/or tubular injury, in part through decreased PRKCI. The induction of OASIS in podocytes is a critical event for the disturbance of kidney homeostasis.
2022-06-22 | GSE206525 | GEO
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.
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Project description:we profiled GEC mRNA expression levels in two animal models with podocyte depletion. We used a transgenic mouse model with YFP-labelled GEC for sorting of GEC. Podocyte depletion was induced by injection of mice with a specific anti-podocyte antibody or crossing with a podocyte-specific doxycycline-induced diphtheria toxin A (DTA) expression transgenic mouse model. Both mouse models developed significant proteinuria, glomerulosclerosis, and podocyte depletion. YFP-positive GECs were sorted from these mice for RNA sequencing. Analysis of the differentially expressed genes (DEGs) between the diseased and control mice revealed significant alteration of metabolism and immune system in the antibody-mediated podocyte depletion model while angiogenesis, vascular development, actin cytoskeleton, and focal adhesion pathways were highly enriched in the DTA model. Apoptosis and cell adhesion pathways were enriched in both models. Apoptosis of GEC was confirmed in the kidney of these mice, which leads to the reduction of GEC number. We also identified a list of genes which were altered in both animal models. Among them, we have further validated Cd63, a molecule which is regulated in human DKD and plays a key role in endothelial cell function. In conclusion, this is the first unbiased approach to determine the genomic-wide response of GEC to podocyte depletion in two different animal models. Our study proves that podocyte depletion could induce GEC injury.
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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.
2023-04-10 | GSE186258 | GEO
Project description:Single cell transcriptomics reveal disrupted kidney filter cell-cell interactions after early and selective podocyte injury
| PRJNA728307 | ENA
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.
2023-07-20 | PXD029618 | Pride
Project description:Podocyte injury is a major determinant in proteinuric kidney disease and identification of potential therapeutic targets for preventing podocyte injury has clinical importance. Here, we show that histone deacetylase Sirt6 protects against podocyte injury through epigenetic regulation of Notch signaling. Sirt6 is downregulated in renal biopsies from patients with podocytopathies and its expression negatively correlates withglomerular filtration rate. Podocyte-specific deletion of Sirt6 exacerbates podocyte injury and proteinuria in two independent mouse models including diabetic nephropathy and adriamycin-induced nephropathy. Sirt6 has pleiotropic protective actions in podocytes including anti-inflammatory and anti-apoptotic effects, is involved in actin cytoskeleton maintenance, and promotes autophagy. Sirt6 also reduces urokinase plasminogen activator receptor expression, which is a key factor for podocyte foot process effacement and proteinuria. Mechanistically, Sirt6 inhibits Notch1 and Notch4 transcription by deacetylating the histone H3K9. We suggest Sirt6 as a potential therapeutic target in proteinuric kidney disease.
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Project description:In the context of human disease, the mechanisms whereby transcription factors reprogram gene expression in reparative responses to injury are not well understood. We have studied the mechanisms of transcriptional reprogramming in disease using murine kidney podocytes as a model for tissue injury. Podocytes are a crucial component of glomeruli, the filtration units of each nephron. Podocyte injury is the initial event in many processes that lead to End Stage Kidney Disease. FOXC2 is a transcription factor known to regulate gene expression in podocytes. FOXC2 and WT1 are both required for podocyte differentiation. Using murine models and human kidney organoids, we investigated FOXC2-mediated transcriptional reprogramming during the course of podocyte injury. Correlating FOXC2 and WT1 ChIP-seq analyses demonstrated that they co-bind many genes expressed in podocytes. Reprogramming the transcriptome involved highly dynamic changes in the binding of FOXC2 and WT1 to target genes during a reparative injury response.
2023-11-01 | GSE213174 | GEO
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.
2023-12-01 | GSE227414 | GEO
Project description:Podocytes are essential cells of the renal blood filter. They structurally compose the renal blood filter by interdigitating with neighboring podocytes by the means of a modified adherens junction, the slit membrane. In podocyte injury, loss of podocytes is a common feature. Podocyte loss could be mediated by the cleavage of podocyte cell adhesion molecules through the A Disintegrin and Metalloproteinase 10 (ADAM10). Here we show that ADAM10 is highly abundant at the site of blood filtration, namely at podocyte foot processes. Podocyte-expressed ADAM10 is not required for the development of the renal filter but plays a major role in podocyte injury. Following antibody-mediated injury, ADAM10 is upregulated in humans and mice. ADAM10 activity results in the cleavage of cell-cell adhesion molecules. This cleavage paves the way for an activation of the injury related Wnt/-catenin signaling pathway and for podocyte loss. We therefore conclude that ADAM10-mediated ectodomain shedding of injury-related cadherins drives podocyte injury. As part of this project, we have analyzed the membrane proteome of murin podocytes to evaluate the abundance of membrane bound proteases.
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