Similar Datasets
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:Human podocyte cell line mRNA-seq
| PRJNA799115 | ENA
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.
2021-02-19 | PXD022213 | Pride
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.
2021-06-01 | GSE128736 | GEO
Project description:Podocyte injury in Fabry nephropathy
| PRJNA773084 | ENA
Project description:We compared mRNA profiles of isolated glomeruli versus sorted podocytes between diabetic and control mice. IRG mice crossed with eNOS-/- mice were further bred with podocin-rTTA and TetON-Cre mice to permanently label podocytes before the diabetic injury. Diabetes was induced by injection of streptozotocin. mRNA profiles of isolated glomeruli and sorted podocytes from diabetic and control mice at 10 weeks after induction of diabetes were examined. Consistent with the previous reports, expression of podocyte-specific markers in the glomeruli were down-regulated in the diabetic mice compared to controls. However, these differences disappeared when mRNA levels were corrected for podocyte number per glomerulus. Interestingly, the expression of these markers was not altered in sorted podocytes from diabetic mice, suggesting that the reduced expression of podocyte markers in isolated glomeruli is likely a secondary effect of reduced podocyte number, rather than the loss of differentiation markers. Analysis of the differentially expressed genes in diabetic mice also revealed distinct up-regulated pathways in the glomeruli (mitochondrial function and oxidative stress) and podocytes (actin organization). In conclusion, our data suggest that podocyte-specific gene expression in transcriptome obtained from the whole glomeruli may not represent those of podocytes in the diabetic kidney. We compared mRNA profiles of isolated glomeruli versus sorted podocytes between diabetic and control mice.
2016-03-16 | E-GEOD-79291 | biostudies-arrayexpress
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: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.
2017-06-20 | GSE100185 | GEO
Project description:Purpose:Renal injury with the loss of podocyte was characteristic pathology of diabetic nephropathy (DN) and correlated with increased albuminuria. Many studies have found the nephroprotective effect of the novel inhibitors of sodium-glucose cotransporter 2 (SGLT2-is), like Dapagliflozin, delaying the progression of DN. However, the underlying mechanisms of SGLT2 associated with podocyte injury are still not fully elucidated. Methods: Through mRNA sequencing, streptozotocin-induced and Dapagliflozin-intraperitoneal injection mice models were established to explore potential mechanism between Dapagliflozin and renal phenotype. And all changes referring this observed pathway were proven repeatedly in podocyte. Results: Here, we generated the streptozotocin-induced DN models and found the accumulation of nephrotoxin and pathological lesions of the kidney, including interstitial inflammatory infiltration, mesangial expansion and glomerular sclerosis, while low expression of SGLT2 mitigated these injuries in Dapagliflozin-treated mice. Moreover, mRNA expression profile in these treated models determined the significance of insulin-like growth factor-1 receptor (IGF1R)/PI3K regulatory axis in glomerular injury. Particularly, SGLT2-is inhibited the increase of mesenchymal marker, α-SMA and the decrease of podocyte marker, nephrin at the gene or protein level. KEGG analysis also showed the enrichment of phosphatidylinositol signaling system and TGF-β/smad pathway. In parallel, the protein level of IGF1R, phosphorylated PI3K, and α-SMA were increased in high-glucose stimulated human podocyte, and reduced in Dapagliflozin (50nM and 100nM) or OSI-906 (inhibitor of IGF1R, 60nM) used groups. Notably, combination of the two inhibitors produced an accumulative effect in the protection of podocyte integrity. Mechanistically, IGF1 or IGF2 could bind to IGF1 receptors to mediate the epithelial-mesenchymal transition (EMT) of diabetic podocyte in response to the upregulation of SGLT2. Indeed, we enrolled the urine and plasma samples from a cohort consisting of 13 healthy people, and a cohort of 19 patients with DN using SGLT2-inhibitors (n=9) or not (n=10). Compared with pure DN patients, Elisa results suggested an increased circulation and excretion level of IGF1/2 in SGLT2-is used DN cohort. Conclusions: Taken together, our study reported the key role of SGLT2/IGF1R/PI3K signaling in regulating podocyte EMT. Modulating the IGF1R expression may provide a novel idea for DN therapy.
2022-10-19 | GSE200322 | GEO
Project description:Podocyte injury that compromises the glomerular filtration barrier is an initiating feature of chronic kidney disease. Podocytes extend major cytoplasmic projections that ultimately subdivide into interdigitating foot processes to form a scaffold that supports the glomerular filtration barrier. We investigated whether podocytes, like other cell types that elaborate complex cytoplasmic projections, utilize RNA transport and local translation in order to synthesize proteins at sites distal from the cell body. Here we show that mice deficient in the RNA binding proteins Staufen1 and 2 are significantly more sensitive to podocyte injury. Furthermore, Staufen2 associates with the podocyte cytoskeleton and is present in foot processes. After injury, Staufen2 and translating ribosomes increase markedly in areas of effacement adjacent to the glomerular basement membrane. Lastly, we found that Staufen2-bound RNAs are enriched in those encoding proteins mediating cytoskeletal assembly and cell-matrix adhesion. RNA transport and localized translation is identified as a crucial process for maintaining the glomerular filtration barrier.
2022-09-01 | GSE85485 | GEO