Tubular injury has been shown to play a critical role in the morbidity of diabetic kidney disease (DKD); ferroptosis often occurs in tubules during renal disease development. This study was aimed at evaluating the inhibitory effects and potential mechanism of dapagliflozin (DAPA) against diabetic-related ferroptosis in the kidney. C57BL/6 mice were fed a high-fat diet (HFD) for 12 weeks, administered a small dose of streptozocin (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. The effects of DAPA were also evaluated in HK-2 cells subjected to simulated diabetic conditions through excess glucose or palmitic acid (PA) administration. DAPA significantly ameliorated tubular injury independently of glycemic control in diabetic model mice. 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 and may consequently reduce ubiquitination degradation. In conclusion, in this study, the tubular protective effects of DAPA, irrespective of glycemic control, were observed in a diabetic mouse model. DAPA ameliorated ferroptosis during diabetic tubular injury via SLC40A1 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 DAPA in the treatment of DKD.
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