Rhein attenuates obesity-related glomerulopathy by inhibiting the P۲X۷R/NLRP۳ inflammasome pathway and protecting podocytes

Objective(s): To investigate the renoprotective effects of Rhein in obesity-related glomerulopathy (ORG) by inhibiting the P۲X۷ receptor (P۲X۷R)/NOD-like receptor protein ۳ (NLRP۳) inflammasome pathway.Materials and Methods: ORG was induced in C۵۷BL/۶J mice with a high-fat diet (HFD) for ۱۰ weeks, fol-lowed by oral Rhein treatment (۷۰ or ۳۰۰ mg/kg/day) for ۱۰ weeks. Renal function, histology, and podocyte injury were assessed. In vitro, leptin-induced podocyte injury was treated with Rhein or P۲X۷R antagonists (KN-۶۲ or A-۴۳۸۰۷۹). P۲X۷R/NLRP۳ activation, inflammation, and oxidative stress were evaluated.Results: HFD-induced weight gain, dyslipidemia, renal dysfunction, glomerular hypertrophy, and podocyte injury. Rhein reduced serum triglycerides (TG) and total cholesterol (TC), lowered blood urea nitrogen (BUN), improved urinary protein excretion, and alleviated histological damage. Rhein inhibited P۲X۷R and NLRP۳ activation, down-regulated caspase-۱, interleukin (IL)-۱β, and IL-۱۸, and restored podocyte markers (Nephrin, Podocin). In vitro, Rhein mitigated leptin-induced podocyte injury and inflammasome activation.Conclusion: Rhein protects against ORG by suppressing the P۲X۷R/NLRP۳ pathway, reducing inflammation and oxidative stress, and preserving podocyte integrity, highlighting its therapeutic potential.

کلیدواژه ها:

Inflammation ، Leptin ، NLRP۳ inflammasome ، Obesity-related- glomerulopathy ، P۲X۷ receptor ، Podocyte ، Rhein