Dapagliflozin alleviates renal fibrosis in type 2 diabetic mice through regulating STAT3

Dapagliflozin, pharmacologically categorized as a sodium-glucose co-transporter 2 blocking agent, has demonstrated therapeutic efficacy in type 2 diabetes. However, its capacity and underlying mechanisms to ameliorate renal fibrosis secondary to type 2 diabetes, remains an area of ongoing investigation. Theobjectiveofthis research was to explore how dapagliflozin exerts its therapeutic effects when applied todiabetic mouse models created through high-fat diet in conjunction with streptozotocin, and renal tubular epithelial cells exposed to hyperglycemic conditions. In addition, metformin served as the reference compound in our study. Histopathological staining analyses revealed glomerulosclerosis and collagen deposition within renal tissue of diabetic nephropathy mice, indicative of renal fibrosis. Notably, dapagliflozin treatment exhibited a dose-related decrease in fibrosis biomarkers expression-specifically Matrix Metallopeptidase 2, Transforming Growth Factors 1, phosphorylated Smad2/3, collagen III and α-smooth muscle actin in both animal models and renal tubular epithelial cells. Further research indicates that this inhibitory effect on fibrosis may be attributed to dapagliflozin's capacity to impede Signal transducer and activator of transcription 3 (STAT3) phosphorylation and its resultant migration to the nucleus. To confirm this hypothesis, the STAT3 knockdown experiment was conducted. The findings indicated that STAT3 knockdown markedly suppressed the expression of renal fibrosis-associated markers, thereby effectively mitigating the fibrotic in kidney tubular epithelial cells. Ultimately, this study underscores the beneficial impact of dapagliflozin on diabetes-induced kidney fibrosis by preventing the activation and phosphorylation of STAT3.