Saracatinib, a Src kinase inhibitor, enhances the renoprotective effect of metformin and losartan in diabetic nephropathy

Objective: This research assesses renoprotective effects of saracatinib (Src) in diabetic nephropathy (DN) and the potential underlying processes.

Materials and methods: Rats were divided into: control, DN, DN + Met + Los, DN + Met + Src, and DN + Met + Los + Src. Rats' ABP, urinary albumin, urinary nephrin, and creatinine clearance were assessed. Blood samples were collected for measuring glycaemic state parameters, renal functions, oxidative stress markers, inflammatory mediators, aldosterone, and lipid profile. Kidneys were extracted for KIM-1 and nephrin gene expression, H&E, Masson's trichrome staining, and immunohistochemical assessment.

Results: Significant increases in ABP, urinary albumin and nephrin, glycaemic measurements, urea, creatinine, aldosterone, inflammatory cytokines, MDA, lipids, renal fibrosis, H scores of VEGF and TGF-β, and renal KIM-1 expression were related to DN. However, there was a significant decrease in creatinine clearance, GSH, and nephrin expression in DN group compared with control group.

Discussion and conclusion: The combination of metformin (Met), losartan (Los), and Src repaired DN alterations. Adding Src to Met and Los is superior to using them alone.