Effect of SIRT6 on renal tubular cells in diabetic kidney disease [CUT&Tag]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE291844 | GEO | 2026/07/08
REPOSITORIES: GEO
Dataset's files
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| GSE291844_RAW.tar | Raw | |||
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Project description:To explore the role of SIRT6 in renal tubular epithelial cells in DKD mice, we extracted primary renal tubular epithelial cells from wild-type and tubular epithelial SIRT6-specific knockout DKD mice, respectively.
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Project description:Diabetic kidney disease (DKD) has become the leading cause of end-stage renal diseases, but the efficacy of current treatment remains unsatisfactory. The pathogenesis of DKD needs a more in-depth research. Ubiquitin specific proteases 36 (USP36), a member of deubiquitinating enzymes family, has aroused wide concerns for its role in deubiquitinating and stabilizing target proteins. Nevertheless, the role of USP36 in diabetes has never been reported yet. Herein, we identified an increased expression of USP36 both in vitro and in vivo in diabetic renal tubular epithelial cells (TECs), and its overexpression is related to the enhanced epithelial-to-mesenchymal transition (EMT). Further investigation into the mechanisms proved that USP36 could directly bind to and mediate the deubiquitination of dedicator of cytokinesis 4 (DOCK4), a guanine nucleotide exchange factor (GEF) that could activate Wnt/β-catenin signaling pathway and induce EMT. Our study revealed a new mechanism that USP36 participates in the pathogenesis of DKD, and provided potential intervening targets accordingly.
2021-09-09 | PXD023347 | Pride
Project description:Background: Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease worldwide with limited treatment options. The intricate pathogenesis of dysregulated lipid metabolism leading to the development of DKD remains obscure. Lipophagy, which refers to the autophagic degradation of intracellular lipid droplets, has been found to be impaired in DKD, resulting in renal tubule dysfunction and ectopic lipid deposition (ELD). The lipotoxity in renal tubules is closely related to the pathogenesis of DKD. Therefore, it is crucial to develop effective and safe agents that can restore autophagic flux and lipophagy in renal tubules for potential preventive interventions. Purpose: This study seeks to investigate the preventive effect of sodium butyrate (NaB) on ELD in the progression of DKD and elucidate the underlying mechanisms involved.Methods: The beneficial effects of NaB were investigated in glucolipotoxicity (GLT)-stimulated HK-2 cells and the streptozotocin (STZ) injection combined with a high-fat diet induced DKD model mice. Additionally, we managed to silence transcription factor EB (TFEB) in HK-2 cells and establish the renal specific silence model by retrograde ureteral infusion of AAV9-shTFEB in mice. We investigated the expression profile of RNAs in HK-2 cells through. The mechanism of NaB is demonstrated by RNA sequencing (RNA-seq), pulldown MS assay, SPR experiments etc.Results: Our findings revealed that serum butyrate level is reduced in DKD patients and is statistically correlated with urinary protein excretion and eGFR. Sodium butyrate (NaB) dose-dependently improved lipid deposition in HK-2 cells and renal tubular epithelial cells of DKD model mice. This effect may be attributed to the promotion of TFEB dephosphorylation, as NaB can directly interact with PPP2R1A to activate PP2A phosphorylation activity. Therefore, NaB may play a role in improving renal lipid deposition in DKD through the PP2A-TFEB pathway. Conclusion: NaB acts as a PP2A-TFEB axis activator that restores lipophagy to ameliorate ELD and renal dysfunction in DKD.
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Project description:To assess the renal tubular condition in DKD patients，
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Project description:Exercise is an effective intervention for diabetic nephropathy (DN), but its molecular mechanisms remain incompletely understood. Here, we identify cysteine dioxygenase type 1 (Cdo1) as a mediator of exercise-induced renal protection. Exercise upregulates renal tubular Cdo1 expression via the α-ketoglutarate-TET-DNA demethylation pathway. Tubular epithelial cell-specific deletion of Cdo1 exacerbates DN and attenuates exercise-mediated alleviation of DN, whereas Cdo1 overexpression improves renal function and synergizes with exercise in ameliorating DN. Mechanistically, tubular Cdo1 promotes taurine production, which suppresses macrophage glycolysis and inflammatory activation by disrupting PKM2-HIF-1α interaction. Taurine supplementation rescues kidney injury in Cdo1-deficient mice, and alleviates DN in synergy with exercise. Thus, exercise ameliorates DN through Cdo1-mediated metabolic crosstalk between renal tubules and macrophages via the taurine-PKM2-HIF-1α axis.
2026-06-09 | GSE334164 | GEO
Project description:The target gene of EP300 action was detected in human renal tubular epithelial cells
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Project description:Adipokines serve crucial functions in diabetic kidney disease (DKD) pathogenesis. Growth differentiation factor 5 (GDF5) is highly expressed in adipose tissue, but its specific role in DKD is unknown. In this study, we observed elevated GDF5 expression in both DKD patients and db/db mice, suggesting a potential association between GDF5 and DKD progression. Elevated plasma GDF5 levels are associated with an increased risk of incident CKD in patients with type 2 diabetes mellitus. In animal studies, adipose-specific overexpression of GDF5 increased circulating GDF5 and exacerbated renal injury in db/db mice, characterized by increased tubulointerstitial injury and inflammation infiltration. Conversely, adipose-specific knockdown reduced circulating GDF5 and alleviated renal injury. In vitro studies demonstrated that GDF5 induces partial epithelial-mesenchymal transition (pEMT) in renal tubular epithelial cells via activation of the SMAD1/5/8 signaling pathway, as evidenced by reduced E-cadherin expression and increased Snail1 levels. Notably, the supernatant from GDF5-treated injured HK-2 cells was found to enhance the secretion of pro-inflammatory cytokines by macrophages. These findings suggest that adipose-derived GDF5 acts as a novel mediator contributing to tubulointerstitial injury in DKD.
2026-06-30 | GSE301094 | GEO
Project description:Persistently enhancement of glycolytic activity has been increasingly implicated as a key contributor to the development of diabetic kidney disease (DKD). Lactate, the end product of glycolysis, can trigger histone lactylation, —an emerging epigenetic modification involved in regulating gene expression, yet its functional significance in DKD remains largely unclear. Here, we observed that 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a key glycolytic enzyme, was remarkably induced in tubular epithelial cells (TECs) in both DKD patients and mice model. Inhibition the expression of PFKFB3 mitigated kidney fibrosis, and preserved kidney function in DKD mice model. Conversely, upregulation of PFKFB3 aggravates renal fibrogenesis and promotes the deterioration of renal pathology. Moreover, we demonstrated that reducing the lactate levels markedly alleviated renal fibrosis in DKD. Mechanistically, lactate generated via PFKFB3-driven glycolytic reprogramming selectively enhances H4K12 lactylation at the HIPK2 promoter, thereby activating its transcription and driving renal fibrotic progression. These findings suggest that tubular PFKFB3 enhancing HIPK2 expression by promoting H4K12la-mediated gene transcription. Thus, targeting the PFKFB3-mediated HIPK2 activation in renal tubular cells could be a novel strategy for DKD.
2026-04-22 | GSE328635 | GEO
Project description:Cellular senescence plays a critical role in diabetic nephropathy (DN). Understanding the mechanisms underlying the senescence response is therefore essential for developing effective therapies for DN. In this study, we provide evidence that NAT10 expression was markedly elevated in the kidney tissues of patient with DN and was associated with adverse clinical outcomes. NAT10 directly bound to PAPP-A, induced ac4C acetylation modification of the PAPP-A transcript, and enhanced its stability, thereby promoting PAPP-A upregulation. Moreover, NAT10-mediated ac4C acetylation accelerated renal tubular epithelial cell senescence in DN through the PAPP-A/p53 pathway. Conditional knockout (cKO) of NAT10 attenuates renal tubular senescence in streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM) mouse models. Renal tubular-specific knockdown of NAT10 via targeted adeno-associated virus ameliorates renal tubular epithelial cell senescence in db/db mouse models of type 2 diabetes mellitus (T2DM). Pharmacological inhibition of NAT10 with Remodelin protects against renal tubular epithelial cell senescence both in vivo and in vitro. In conclusions, NAT10-mediated ac4C acetylation contributes to renal tubular epithelial cell senescence in DN and that NAT10-regulated PAPP-A could be a promising and feasible therapeutic target in DN.
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Project description:To find miRNAs that involve in renal epithelial-mesenchyal transition induced by TGFbeta Mouse renal tubular cell, MCT (derived from SJL H-2S mice) was stimulated by TGFbeta 3ng/ml for 72 hours. miRNA expressions were compared with control.
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