SGLT2 inhibition attenuates diabetes-induced lipid nephrotoxicity by targeting SOAT1-mediated cholesterol metabolism in proximal tubular cells.

Diabetic kidney disease (DKD) is a severe complication of diabetes mellitus and a leading cause of end-stage kidney disease (ESKD). Ectopic lipid accumulation, particularly cholesterol deposition in renal proximal tubular cells, contributes to tubular dysfunction and progression of DKD. This study explored the effects of dapagliflozin (DAPA), a sodium-glucose cotransporter 2 inhibitor, on cholesterol metabolism in renal proximal tubular cells. Using db/db diabetic mice, we found that DKD was associated with renal dysfunction, tubular injury, and marked cholesterol accumulation in proximal tubules. In addition to reducing urinary albumin-to-creatinine ratio (UACR), DAPA improved renal function indices, attenuated tubular injury, and reduced both free and esterified cholesterol accumulation in renal tubular cells. Double immunofluorescence staining further confirmed that sterol O-acyltransferase 1 (SOAT1) was predominantly localized in proximal tubular epithelial cells and was markedly upregulated in db/db mice, whereas DAPA treatment suppressed this increase. In vitro studies in HK-2 cells showed that DAPA reduced cholesterol accumulation by inhibiting SOAT1-mediated cholesterol esterification and enhancing ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux. Mechanistically, SOAT1 knockdown mimicked the protective effect of DAPA, whereas SOAT1 overexpression largely abolished it. Moreover, DAPA and SOAT1 silencing attenuated high glucose-induced apoptotic injury, as evidenced by reduced Annexin V/PI positivity and decreased cleaved caspase-3 and cleaved PARP expression. These results suggest that DAPA mitigates renal injury and slows DKD progression by modulating cholesterol homeostasis in proximal tubular cells. Our findings support a novel mechanism by which DAPA protects against diabetes-induced lipid nephrotoxicity through suppression of SOAT1-dependent cholesterol esterification and restoration of ABCA1-mediated cholesterol efflux.