Aims: Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) showed excellent renoprotective effects; however, the underlying mechanism remains not fully understood. Previous studies have revealed the importance of ferroptosis, which is closely related to oxidative stress, in the progression of DKD. In the current study, we hypothesized that SGLT2i could relieve ferroptosis and thereby alleviate renal injury in DKD due to their antioxidative stress effects. Results: Typical changes of ferroptosis including massive lipid peroxidation, compromised antioxidant capability, and iron overload were found in db/db mice and high glucose/high fat (HG/HF)-treated HK-2 cells. Furthermore, increased expression of hypoxia inducible factor 1α (HIF1α) and heme oxygenase 1 (HO1) was observed in db/db mice and HG/HF-treated HK-2 cells as well. Dapagliflozin treatment significantly ameliorated the ferroptosis-related changes via attenuating overactivation of the HIF1α/HO1 axis in vivo and in vitro. Besides, downregulation of the HIF1α/HO1 axis alleviated ferroptosis, while overexpression of HIF1α and HO1 aggravated ferroptosis induced by HG/HF in HK-2 cells. Innovation and Conclusion: This study revealed that SGLT2i played a renoprotective role in DKD, at least in part, through alleviating HIF1α/HO1-mediated ferroptosis. Antioxid. Redox Signal. 40, 492-509.
Keywords: SGLT2 inhibitor; dapagliflozin; diabetic kidney disease; ferroptosis; heme oxygenase 1; hypoxia inducible factor 1α.