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ABSTRACT:
PROVIDER: PRJNA1307071 | ENA |
REPOSITORIES: ENA
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Project description:<p>Chronic kidney disease (CKD) is a major health issue, with podocyte injury with senescence playing a central role in glomerulosclerosis. This study investigates the link between glycolysis-derived serine metabolism and podocyte injury with senescence, focusing on the role of phosphoglycerate kinase 1 (PGK1) in the regulation of L-serine synthesis and podocyte homeostasis. Using in vivo and in vitro models, we examined the effects of angiotensin II (Ang II)-induced metabolic dysregulation on serine metabolism and its impact on podocyte function. The results demonstrate that Ang II downregulates PGK1 expression through the transcription factor FOXA1, leading to reduced L-serine biosynthesis, mitochondrial dysfunction, and increased cellular senescence in podocytes. Supplementing with L-serine or enhancing PGK1 expression in podocytes alleviated these pathological changes, restored mitochondrial function, and reduced senescence-associated phenotypes in CKD mouse models. Moreover, PGK1 was found to interact with keratin, type II cytoskeletal 1 (KRT1), stabilizing the cytoskeletal integrity of podocytes. These findings identify a novel metabolic pathway linking glycolysis, serine metabolism, and podocyte injury with senescence, suggesting that targeting the PGK1-serine axis may offer therapeutic potential for slowing podocyte senescence and CKD progression.</p>
2025-08-23 | MTBLS12883 | MetaboLights
Project description:Vascular endothelial cells (ECs) senescence correlates with the increase of cardiovascular diseases in ageing population. Although ECs rely glycolysis for energy production, little is known about the role of glycolysis in ECs senescence. Here, we report a critical role for glycolysis-derived serine biosynthesis in preventing ECs senescence. During senescence, the expression of serine biosynthetic enzyme PHGDH is significantly reduced due to decreased transcription of the activating transcription factor ATF4, which leads to decreased intracellular serine. PHGDH prevents premature senescence primarily by enhancing the stability and activity of pyruvate kinase M2 (PKM2). Mechanistically, PHGDH interacts with PKM2, which prevents PCAF-catalyzed PKM2 K305 acetylation and subsequent degradation by autophagy. In addition, PHGDH facilitates p300-catalyzed PKM2 K433 acetylation, which promotes PKM2 nuclear translocation and stimulates its activity to phosphorylate H3T11 and regulate the transcription of senescence-associated genes. Vascular endothelium-targeted expression of PHGDH and PKM2 ameliorates the mice ageing phenotype. Our findings reveal that enhancing serine biosynthesis could become a novel therapy to promote healthy ageing.
2023-05-10 | PXD035586 | Pride
Project description:Vascular endothelial cells (ECs) senescence correlates with the increase of cardiovascular diseases in ageing population. Although ECs rely glycolysis for energy production, little is known about the role of glycolysis in ECs senescence. Here, we report a critical role for glycolysis-derived serine biosynthesis in preventing ECs senescence. During senescence, the expression of serine biosynthetic enzyme PHGDH is significantly reduced due to decreased transcription of the activating transcription factor ATF4, which leads to decreased intracellular serine. PHGDH prevents premature senescence primarily by enhancing the stability and activity of pyruvate kinase M2 (PKM2). Mechanistically, PHGDH interacts with PKM2, which prevents PCAF-catalyzed PKM2 K305 acetylation and subsequent degradation by autophagy. In addition, PHGDH facilitates p300-catalyzed PKM2 K433 acetylation, which promotes PKM2 nuclear translocation and stimulates its activity to phosphorylate H3T11 and regulate the transcription of senescence-associated genes. Vascular endothelium-targeted expression of PHGDH and PKM2 ameliorates the mice ageing phenotype. Our findings reveal that enhancing serine biosynthesis could become a novel therapy to promote healthy ageing.
2023-05-10 | PXD035585 | Pride
Project description:Podocyte histone deacetylases (HDAC) are essential in maintaining a normal glomerular filtration barrier by modulating podocyte quiescence. Podocyte-specific loss Hdac1 and 2 in mice results in severe proteinuria and sustained DNA damage, likely caused by epigenetic alterations and deficient DNA repair, that result in podocyte senescence. Through glomeruli isolation and RNA-seq profiling from the mutant mice, we demonstrated that senescent podocytes develop a senescence-associated secretory phenotype (SASP) that contribute to the loss of podocytes. The role of HDACs in senescence may provide important clues in our understanding of how podocytes are lost following injury.
2022-10-25 | GSE216088 | GEO
Project description:Alport syndrome (AS) is a hereditary kidney disease with no curative treatment, which characterized by hematuria, proteinuria, and progressive kidney failure. Podocyte injury has been observed in AS, whereases, the mechanism is still unclear. Reported studies showed the expression level of secreted protein acidic and rich in cysteine (SPARC) correlated with podocyte injury in chronic kidney diseases, yet its mechanism still unknown. Especially, its role in AS-related podocyte injury is unclear. Therefore, the kidney of Col4a3-/- AS mice was used to detect SPARC expression, location, and podocyte injury, and mouse podocyte cell line (MPC5) was used to explore the mechanism of SPARC-induced podocyte injury. Besides, SPARC expression in both urine and kidney samples from AS patients were analyzed. The results showed, SPARC upregulated and located in podocytes were detected in Col4a3-/- AS mice, and increased inflammatory cytokines, impaired podocyte structure and function were identified in SPARC-overexpression MPC5, importantly, knockdown adhesion G protein-coupled receptor B1 (ADGRB1) exerted a protective effect. In AS patients, urinary increased level of SPARC was detected, SPARC deposition in glomeruli of kidney sections was identified. Our findings identified SPARC as a key mediator of podocyte injury in AS, with ADGRB1 acting as its downstream effector.
2025-10-04 | GSE309489 | GEO
Project description:Patients with hypertension or obesity can develop glomerular dysfunction characterized by injury and depletion of podocytes. To better understand the molecular processes involved, young mice were treated with either deoxycorticosterone acetate (DOCA) or fed a high-fat diet (HFD) to induce hypertension or obesity, respectively. The transcriptional changes associated with these phenotypes were measured by unbiased bulk mRNA-sequencing of isolated podocytes from experimental models and their respective controls. Key findings were validated by immunostaining. In addition to a decrease in canonical proteins and reduced podocyte number, podocytes from both hypertensive and obese mice exhibited a sterile inflammatory phenotype characterized by increases in NLRP3 inflammasome, protein cell death-1, and Toll-Like Receptor pathways. Finally, although the mice were young, podocytes in both models exhibited increased expression of senescence and aging genes, including genes consistent with a senescence-associated secretory phenotype. However, there were differences between the hypertension- and obesity-associated senescence phenotypes. Both show stress-induced podocyte senescence characterized by increased p21 and p53. Moreover, in hypertensive mice, this is superimposed upon age-associated podocyte senescence characterized by increased p16 and p19. These results suggest that senescence, aging, and inflammation are critical aspects of the podocyte phenotype in experimental hypertension and obesity in mice.
2024-07-03 | GSE255723 | 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.
2025-03-17 | GSE281894 | 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:Proliferating tumor cells use aerobic glycolysis to support their high metabolic demands. Paradoxically, increased glycolysis is often accompanied by expression of the lower activity PKM isoform, effectively constraining lower glycolysis. Here, we report the discovery of novel PKM activators with a unique allosteric binding mode. Characterization of how these compounds impact cancer cells revealed an unanticipated link between glucose and amino acid metabolism. PKM activation resulted in a metabolic rewiring of cancer cells manifested by a profound dependency on the non-essential amino acid serine for continued cell proliferation. Induction of serine auxotrophy by PKM activation was accompanied by reduced carbon flow into the serine biosynthetic pathway and increased expression of high affinity serine transporters. These data support the hypothesis that PKM expression confers metabolic flexibility to cancer cells that allows adaptation to nutrient stress. A549 cancer cells were treated with compound-16 for up to 24 hours in the presence and absence of serine in the media.
2012-12-20 | E-GEOD-40191 | biostudies-arrayexpress
Project description:Liver injury results in rapid regeneration through hepatocyte proliferation and hypertrophy. However, after acute severe injury, such as acetaminophen poisoning, effective regeneration may fail. We investigated how senescence underlies this regenerative failure. In human acute liver disease, and murine models, p21-dependent hepatocellular senescence was proportionate to disease severity and was associated with impaired regeneration. In an acetaminophen injury model a transcriptional signature associated with the induction of paracrine senescence is observed within twenty four hours, and is followed by one of impaired proliferation. In genetic models of hepatocyte injury and senescence we observed transmission of senescence to local uninjured hepatocytes. Spread of senescence depended upon macrophage derived TGFβ1 ligand. In acetaminophen poisoning inhibition of TGFβ receptor 1 (TGFβR1) improved survival. TGFβR1 inhibition reduced senescence and enhanced liver regeneration even when delivered after the current therapeutic window. This mechanism, in which injury induced senescence impairs regeneration, is an attractive therapeutic target for acute liver failure.
2019-03-20 | GSE111828 | GEO