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: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.
| S-EPMC11923244 | biostudies-literature
Project description:This RNA-sequencing study investigates the role of SHROOM3 in podocyte function and its contribution to renal pathophysiology. Podocytes are highly specialized epithelial cells critical for glomerular filtration barrier integrity. The study explores how SHROOM3 deficiency affects podocyte cytoskeletal architecture and focal adhesion dynamics in the context of Adriamycin-induced nephropathy, a widely used experimental model of podocyte injury and proteinuric kidney disease. We performed transcriptome analysis using RNA-sequencing on human podocyte cell lines, comparing Control (n=4) and SHROOM3 knockdown (KD) podocytes (n=4). Our objective was to identify the molecular mechanisms and signaling pathways through which SHROOM3 regulates podocyte cytoskeletal organization, with particular focus on stress fiber formation and focal adhesion assembly/disassembly. The dataset provides comprehensive gene expression profiles revealing how SHROOM3 deficiency exacerbates podocyte injury, disrupts actin cytoskeleton dynamics, and impairs focal adhesion stability during nephropathy progression.
2025-04-17 | GSE294734 | GEO
Project description:Podocyte injury in Fabry nephropathy
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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:While the pathogenic role of autoantibodies targeting the podocyte protein THSD7A in membranous nephropathy (MN) is well described, the consequences of autoantibody binding for podocyte homeostasis and the function of THSD7A remain unclear. Here, we induced an MN model in control and podocyte-specific Thsd7a knockout (Thsd7a-/-) mice using rabbit anti-THSD7A antibodies, followed by transcriptome and proteome analyses. Anti-THSD7A antibodies in WT mice caused significant loss of key slit diaphragm (SD) proteins such as nephrin and NEPH1, without transcriptional downregulation. Glomeruli showed substantial transcriptomic and proteomic reconfiguration indicative of extensive podocyte injury, including disruptions in podocyte adhesion, cytoskeletal dynamics, and marked upregulation of ubiquitin-proteasome system components, cathepsins and ADAM proteases. Notably, experiments in C3-deficient mice revealed that proteolytic activation and SD protein loss are driven by complement-independent pathways. While Thsd7a-/- mice only displayed a mild phenotype under basal conditions, they were completely protected from MN development upon anti-THSD7A antibody transfer. Finally, interactomic analysis identified a protein complex including THSD7A and integrin α3, linking THSD7A complexes to pathogenic regulation of cytoskeleton, adhesion, and membrane signaling in MN. Thus, anti-THSD7A antibodies induce profound molecular reconfiguration, including dysregulated proteolytic systems via a complement-independent pathway, revealing potential therapeutic targets in MN.
2026-02-02 | GSE300256 | GEO
Project description:Background: Testican-2 is a podocyte-derived glycoprotein encoded by SPOCK2. Circulating levels of testican-2 are associated with less glomerulosclerosis and better kidney prognosis, but its biological function in the podocyte is unknown. Methods: We studied the protective effect of testican-2 on immortalized cultured human podocytes and in mice treated with adriamycin. We used immunoprecipitation-mass spectrometry to identify binding partners of testican-2 and Bio-Layer Interferometry to characterize these protein-protein interactions. Using global Spock2 knockout mice, we assessed the impact of testican-2 deficiency in models of podocyte injury and also tested whether exogenous testican-2 confers podocyte protection in these testican-2 deficient mice. Finally, we analyzed testican-2 expression in human kidney biopsy samples. Results: Testican-2 reduced reduces adriamycin-induced podocyte injury in cultured human podocytes and mice. Vitronectin is a strong binding partner for testican-2, and testican-2 inhibited inhibits the interaction between vitronectin and integrin αVβ3, an important effector of podocyte injury. Consistent with this, testican-2 administration reduced reduces activation of integrin β3 in injured podocytes. Further, Spock2 deficiency increased increases susceptibility to podocyte injury due to adriamcyin and streptozotocin induced diabetes, as determined by albuminuria, foot process effacement, nephrin expression and WT1-positive podocyte number. Importantly, exogenous testican-2 circulated circulates to the kidney, bound binds to vitronectin, reduced reduces vitronectin-integrin β3 interaction, and reduced reduces podocyte injury in Spock2 deficient mice. Finally, glomerular testican-2 expression was is reduced in human focal segmental glomerulosclerosis and diabetic kidney disease, but not tubulointerstitial nephropathy. Conclusions: These findings identify a potential mechanism for testican-2 mediated kidney protection and highlight an opportunity to therapeutically target the podocyte’s interaction with its extracellular matrix.
2026-01-19 | PXD066935 | Pride
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.
2023-04-10 | GSE186258 | GEO