Dapagliflozin Ameliorates Renal Tubular Ferroptosis in Diabetes via SLC40A1 Stabilization

Tubular injury has been shown to play a critical role in diabetic kidney disease (DKD) morbidity; ferroptosis often occurs in renal tubules during renal disease development. This study aimed to evaluate the inhibitory effects and potential mechanism of dapagliflozin against DKD related ferroptosis. C57BL/6 mice were fed a high-fat diet (HFD) for 12 weeks, administered a small dose of STZ for three consecutive days by intraperitoneal injection, and then orally administered dapagliflozin (10 mg/kg/day) for 8 weeks. Mouse blood and urine samples were collected and their renal cortices were harvested for subsequent investigations. Bioinformatics analysis was performed to determine which signaling pathways were involved in the tubular injury-ameliorating effects of dapagliflozin under diabetic conditions. The effects of dapagliflozin were also evaluated in HK2 cells subjected to simulated diabetic conditions through excess glucose and palmitic acid administration. Dapagliflozin significantly ameliorated tubular injury independently of glycemic control in T2DM model mice. Through the bioinformatics analysis, ferroptosis was found to be involved in the action of dapagliflozin. Furthermore, in vivo and in vitro investigations showed that dapagliflozin ameliorated tubular injury by inhibiting ferroptosis. Docking experiments demonstrated that dapagliflozin and SLC40A1 could bind with each other, consequently reducing acetylation degradation. In conclusion, in this study, the tubular protective effects of dapagliflozin, irrespective of glycemic control, were observed in a T2DM mouse model. Dapagliflozin ameliorated ferroptosis during diabetic tubular injury via ferroportin stabilization, and this may be the mechanism underlying its action. To the best of our knowledge, this is the first study to investigate the ferroptosis inhibitory effects of dapagliflozin in the treatment of DKD.