Dapagliflozin induces renal lipidomic remodeling and systemic metabolic improvement

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease worldwide. Sodium-glucose cotransporter-2 inhibitors (SGLT2is), such as dapagliflozin, have demonstrated renoprotective effects in the treatment of DN. In addition to kidney protection, SGLT2is confer significant cardiovascular and hepatic benefits; however, the mechanisms underlying these multi-organ protective effects have not yet been fully elucidated. A total of 51 patients with newly diagnosed DN were enrolled and received dapagliflozin treatment (10 mg/day; AstraZeneca) for 12 weeks. Circulating lipid profiles were analyzed using untargeted lipidomics. To further characterize renal lipid alterations, spatial metabolomics was performed on kidney tissues obtained from dapagliflozin-treated db/db mice. Dapagliflozin treatment significantly reduced serum triglyceride levels while increasing high-density lipoprotein cholesterol in DN patients. Untargeted lipidomic analysis revealed extensive remodeling of the circulating lipidome, marked by reductions in pro-fibrotic and pro-inflammatory lipid species and concurrent increases in renoprotective lipids, including fatty acid esters of hydroxy fatty acids. Machine-learning analyses identified specific lipid ratio changes that were positively correlated with renal function parameters, notably ratios involving SM(d14:0/30:1) and PC(16:0e/18:2). Furthermore, spatial metabolomic profiling in db/db mice demonstrated that dapagliflozin alleviated renal lipotoxicity by reducing the accumulation of toxic lipid species and promoting lipid redistribution predominantly within the renal cortex. Mechanistically, dapagliflozin treatment was associated with enhanced renal fatty acid β-oxidation and sphingolipid degradation while suppressing key anabolic pathways, including de novo lipogenesis and glycerophospholipid and sphingolipid biosynthesis. These metabolic alterations were further evidenced by altered expression of key regulatory enzymes. Dapagliflozin is associated with remodeling of renal lipid metabolism in DN, accompanied by improvements in systemic lipid profile. The improvement in circulating dyslipidemia may partially explain the cardiovascular and hepatic protective effects associated with dapagliflozin therapy. Collectively, these findings provide mechanistic insight into the lipid-mediated, multi-organ benefits of dapagliflozin in DN.