Dapagliflozin Ameliorates Renal Tubular Ferroptosis in Diabetes via SLC40A1 Stabilization

Abstract

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.

Transcriptomic reveals the ferroptosis features of host response in a mouse model of Zika virus infection

“…Solute carrier family 40 member 1 (SLC40A1), also known as FPN1, is the only iron export protein discovered in mammals, and inhibition of it induces ferroptosis 63 . It has been demonstrated that dapagliflozin (DAPA) improves ferroptosis during diabetic renal tubular injury by stabilizing SLC40A1 64 . The NADPH oxidase CYBB (Nox2) is present in the cellular walls of all vascular walls, and NADPH oxidases (Nox) are the main sources of ROS in the vascular system 65 …”

Role of ferroptosis in chronic kidney disease

“…In MDCK cells, NAC reduced high glucose-induced ferroptosis by increasing GPX4 expression [ 152 ]. Dapagliflozin, a glucose-lowering agent, has been shown to have cardiorenal protective effects, and recent studies have found that dapagliflozin also ameliorated ferroptosis in diabetic tubular injury by stabilizing SLC40A1 [ 153 ]. Empagliflozin also reduced renal tubular cell ferroptosis in DKD by enhancing the AMPK-mediated Nrf2 activation pathway [ 154 ].…”

Targeting ferroptosis as a prospective therapeutic approach for diabetic nephropathy

“…Interestingly, SLC40A1, the only iron export protein discovered in mammals, displayed higher expression in the DAPA group compared to the HG group. The additional experiment proved that SLC40A1 ubiquitination was markedly elevated by HG administration in HK-2 cells but decreased by DAPA therapy, a drug that could directly combine and stabilize SLC40A1 through bioinformatics verification [ 51 ].…”