Effect of SIRT6 on renal tubular cells in diabetic kidney disease
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE291755 | GEO | 2026/07/08
REPOSITORIES: GEO
Dataset's files
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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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2024-10-31 | GSE266108 | GEO
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.
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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.
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Project description:To assess the renal tubular condition in DKD patients，
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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.
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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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