Celastrol attenuates diabetic nephropathy by upregulating SIRT1-mediated inhibition of EZH2related wnt/β-catenin signaling
pubmed: wnt1 2023-09-23
Int Immunopharmacol. 2023 Sep;122:110584. doi: 10.1016/j.intimp.2023.110584. Epub 2023 Jul 14.
Proteinuria is an independent risk factor for the progression of diabetic nephropathy (DN) and an imbalance in podocyte function aggravates proteinuria. Celastrol is the primary active ingredient of T. wilfordii, effective in treating DN renal injury; however, the mechanisms underlying its effect are unclear. We explored how celastrol prevents DN podocyte damage using in vivo and in vitro experiments. We randomly divided 24 male C57BLKS/J mice into three groups: db/m (n = 8), db/db (n = 8), and celastrol groups (db/db + celastrol, 1 mg/kg/d, gavage administration, n = 8). In vivo experiments lasted 12 weeks and intervention lasted ten weeks. Serum samples and kidney tissues were collected for biochemical tests, pathological staining, transmission electron microscopy, fluorescencequantitation polymerase chain reaction, and western blotting analysis. In vitro experiments to elaborate the mechanism of celastrol protection were performed on high glucose (HG)-induced podocyte injury. Celastrol reduced blood glucose levels and renal function index in db/db mice, attenuated renal histomorphological injury and glomerular podocyte foot injuries, and induced significant anti-inflammatory effects. Celastrol upregulated silent information regulator 2 related enzyme 1(SIRT1) expression and downregulated enhancer of zeste homolog (EZH2), inhibiting the wnt/β-catenin pathway-related molecules, such as wnt1, wnt7a, and β-catenin. SIRT1 repressed the promoter activity of EZH2, and was co-immunoprecipitated with EZH2 in mouse podocyte cells (MPC5). SIRT1 knockdown aggravated the protective effects of celastrol on MPC5 cells. Celastrol protected podocyte injury via SIRT1/EZH2, which participates in the wnt/β-catenin pathway. Overall, celastrol-mediated SIRT1 upregulation inhibited the EZH2-related wnt/β-catenin signaling pathway to attenuate DN and podocyte injury, providing a theoretical basis for celastrol clinical application.