Abstract
OBJECTIVES: To investigate the renoprotective effects of Rhein in obesity-related glomerulopathy (ORG) by inhibiting the P2X7 receptor (P2X7R)/NOD-like receptor protein 3 (NLRP3) inflammasome pathway. MATERIALS AND METHODS: ORG was induced in C57BL/6J mice with a high-fat diet (HFD) for 10 weeks, fol-lowed by oral Rhein treatment (70 or 300 mg/kg/day) for 10 weeks. Renal function, histology, and podocyte injury were assessed. In vitro, leptin-induced podocyte injury was treated with Rhein or P2X7R antagonists (KN-62 or A-438079). P2X7R/NLRP3 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 P2X7R and NLRP3 activation, down-regulated caspase-1, interleukin (IL)-1β, and IL-18, 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 P2X7R/NLRP3 pathway, reducing inflammation and oxidative stress, and preserving podocyte integrity, highlighting its therapeutic potential.