Dapagliflozin attenuates diabetes-induced podocyte lipotoxicity via ERRα-Mediated lipid metabolism

Diabetic kidney disease (DKD) is a major complication of diabetes mellitus, characterized by podocyte injury and lipid accumulation, which contribute to high morbidity and mortality. Current treatments primarily alleviate symptoms, underscoring the need for targeted therapies to address the underlying mechanisms of DKD progression. This study explores the protective effects of dapagliflozin (DAPA), a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, on podocyte lipotoxicity and its regulatory role in the estrogen-related receptor alpha (ERRα)-acyl-CoA oxidase 1 (ACOX1) axis. Using db/db mice and streptozotocin-induced DKD models, we demonstrate that DAPA significantly reduces the urinary albumin-to-creatinine ratio (ACR) and improves renal pathology by alleviating glomerular hypertrophy, mesangial matrix expansion, and podocyte foot process effacement. DAPA also decreases triglyceride and free fatty acid accumulation in glomeruli, as evidenced by Oil Red O and BODIPY staining. Mechanistically, DAPA upregulates ERRα and ACOX1 expression in podocytes, enhancing fatty acid oxidation (FAO) and mitigating lipidtoxicity. Loss of ERRα exacerbates lipid-induced podocyte injury, while ERRα overexpression confers protective effects. These findings highlight DAPA’s renoprotective effects via modulation of the ERRα-ACOX1 axis, suggesting that targeting ERRα could be a promising therapeutic strategy for DKD.