NAT10 mediates TLR2 to promote podocyte senescence in adriamycin-induced nephropathy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1186146 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31350361_1.fastq.gz | Fastqsanger.gz | |||
| SRR31350361_2.fastq.gz | Fastqsanger.gz | |||
| SRR31350362_1.fastq.gz | Fastqsanger.gz | |||
| SRR31350362_2.fastq.gz | Fastqsanger.gz | |||
| SRR31350363_1.fastq.gz | Fastqsanger.gz |
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Project description:N-acetyltransferase 10 (NAT10) is involved in regulating senescence. However, its role in glomerular diseases remains unclear. Therefore, this study aims to investigate the mechanisms by which NAT10 influences senescence and damage in an adriamycin (ADR)-induced nephropathy model. Senescence (p16 and p21) and DNA damage markers (γ-H2AX (ser139)) were assessed in ADR-induced nephropathy. NAT10 function was demonstrated using Remodelin or small interfering RNA (siRNA) interventions. Transcriptome sequencing was conducted to identify key downstream genes and pathways, while coimmunoprecipitation was performed to evaluate the relationship between NAT10 and toll-like receptor 2 (TLR2) expression. TLR2 overexpression or knockdown further validated its regulatory role in senescence. In ADR-treated mice, the expression levels of P53, P21, P16, γ-H2AX(S139) proteins were elevated, while those of WT-1 and nephrin were reduced. This effect was mitigated by Remodelin and siNAT10 administration. Transcriptome sequencing identified TLR2 as a key downstream gene, and coimmunoprecipitation, along with molecular docking models, confirmed its interaction with NAT10. TLR2 overexpression plasmid or siRNA was employed for recovery experiments. Together, the study findings suggest that NAT10 contributes to podocyte senescence and injury via interaction with TLR2. Further, it demonstrates that NAT10 alleviates ADR-induced podocyte senescence by interacting with TLR2, potentially through a P53-P21-dependent mechanism. Thus NAT10 could serve as a novel therapeutic target for treating podocyte senescence and proteinuric glomerulopathies.
2025-03-17 | GSE281894 | GEO
Project description:Podocyte injury in Fabry nephropathy
| PRJNA773084 | ENA
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:A central cause of diabetic nephropathy (DN) is podocyte injury. There are many factors causing podocyte injury in DN, such as hyperglycemia, oxidative stress and inflammation. In this study, a signal regulator protein α (SIRPα) was found to play a critical role in regulating podocyte metabolism, oxidative stress and inflammatory.
2024-12-18 | GSE274089 | GEO
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:Purpose: Next-generation sequencing (NGS) was used to identify cellular pathways and genes through systems-based analysis. The goals of this study are to identify NGS-derived transcriptome profiling (RNA-seq) in control (untreated) and Injured (PAN and Adriamycin) podocyte. These high throughput data were further validated through qRT–PCR methods to confirm the cellular pathways and genes affected due to the podocyte injury. Methods: Human podocytes were differentiated for 14 days by thermoswitching from 33⁰C to 37⁰C and removal of growth factors, insulin-transferrin-selenium from the medium. These podocytes were incubated 4hour in serum free RPMI medium and injury was induced by using PAN (100μg/ml) and Adriamycin (0.25μg/ml) treatment for 48 hours.Further, podocytes were processed for RNA isolation and submitted to Medical University of South Carolina Sequencing Core facility for RNA-Seq. All the experiments were performed in triplicates. Conclusions: Our study is first to describe the detailed analysis of PAN and Adriamycin induced podocyte transcriptomes using the RNA-seq technology. A comparative analysis of the differential expression profile was obtained between control vs PAN injured podocytes, and control vs Adriamycin injured podocytes. Complex genetic network and genes effected due to the injury will provide a platform to define biological pathways participate during podocytes injury process.
2019-03-31 | GSE124622 | GEO
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:Transcriptome comparison of glomeruli from kidneys with diabetic nephropathy (DN) and glomeruli from the unaffected portion of tumor nephrectomies. Transcritomics profile of glomeruli in DN patients explored SRGAP2 was strongly associated with proteinuria and involved in podocyte cytoskeleton organization
2018-07-31 | GSE96804 | GEO
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:In this experiment, we aim to examine the role of NAT10 inhibition in Hutchinson-Gilford progeria syndrome (HGPS), a rare but devastating premature ageing syndrome caused by a mutation in the LMNA gene. NAT10 inhibition improves HGPS cellular phenotypes by releasing Transportin-1 (TNPO1) from the cytoplasm, restoring the TNPO1 pathway and allowing hnRNPA1 and NUP153 nuclear import, TPR anchorage at the nuclear pore complexes and RanGTP gradient re-balancing. We have promoted NAT10 inhibition by two ways in normal or patient derived primary skin fibroblasts; the NAT10 inhibitor Remodelin, and an siRNA directly targeting NAT10 (siNAT10). In addition, we have also used an siRNA against TNPO1 and a combined siTNPO1 and siNAT10 treatment. This is a 2-factor design, with treatment (Remodelin vs untreated, or siNAT10 vs siCT) and condition (HGPS vs normal fibroblasts) as the two conditions. Transcriptional profiling was performed using HumanHT-12 v4 Expression BeadChip microarrays, and all conditions were run in triplicate.
2018-06-25 | E-MTAB-6651 | biostudies-arrayexpress