Dapagliflozin inhibits renal mesangial cell fibrosis by regulating HO-1/TGF-β1/Smad 2/3 axis.

Abstract

Diabetic kidney disease (DKD), which is driven by multiple metabolic risk factors, can progress to renal fibrosis and ultimately end-stage renal disease, posing a serious threat to patients with diabetes. Dapagliflozin, a competitive inhibitor of sodium-glucose cotransporter 2, has been reported to alleviate kidney damage and prevent renal failure in patients with diabetes. However, its underlying mechanism remains incompletely understood. In this study, we investigated whether dapagliflozin attenuates renal fibrosis through the heme oxygenase-1 (HO-1)/transforming growth factor-β1 (TGF-β1)/Smad2/3 pathway. We established a diabetic mouse model and assessed renal histopathology and fibrosis-related gene expression. Dapagliflozin attenuated renal fibrosis and downregulated the expression of fibrosis-related markers. Similar antifibrotic effects were observed in palmitic acid (PA)-treated mouse glomerular mesangial SV40 MES 13 cells. Dapagliflozin also upregulated the expression of heme oxygenase-1 (HO-1) protein and gene both in vivo and in vitro. HO-1 overexpression suppressed fibrosis-related marker expression, whereas HO-1 inhibition partially attenuated the protective effects of dapagliflozin in PA-treated mesangial cells. These findings suggest that dapagliflozin exerts its antifibrotic effects, at least in part, by activating HO-1 and eventually suppressing TGF-β1/Smad2/3 signaling in DKD. Collectively, dapagliflozin represents a potential therapeutic strategy for preventing renal fibrosis in DKD.