Liraglutide ameliorates early renal injury by the activation of renal FoxO1 in a type 2 diabetic kidney disease rat model

•Liraglutide can improve renal function in a type 2 diabetic kidney disease rat model.•Liraglutide can inhibit renal fibrosis.•​Liraglutide may exert a renoprotective effect by the activation of FoxO1. The aim of this study was to investigate the effects of liraglutide on renal injury and the renal expression of FoxO1 in type 2 diabetic rats. Type 2 diabetic rats model was induced by a high-sugar and high-fat diet and intraperitoneal injection of low-dose Streptozotocin (STZ) (30 mg/kg). Five weeks after STZ injection, diabetic rats were randomly treated with or without subcutaneous injection of liraglutide (0.2 mg/kg/12 h) for eight weeks. Diabetes-related physical and biochemical indicators, renal histopathological and ultrastructural changes, the expression of renal transforming growth factor beta-1 (TGF-β1), fibronectin (FN), type IV collagen (Col IV), protein kinase B (Akt), forkhead box protein O1 (FoxO1) and manganese superoxide dismutase (MnSOD) were measured. Rats in DN group showed a significant increase in fasting blood glucose, HbA1c, kidney to body weight index, serum creatinine (Scr), blood urea nitrogen (BUN), urinary albumin excretion, mesangial matrix index, glomerular basement membrane (GBM) thickening, podocyte foot process fusion, the mRNA and protein levels of renal TGF-β1, FN and Col IV and a dramatic decrease in the mRNA and protein levels of renal MnSOD, all of which were significantly ameliorated by liraglutide. In addition, liraglutide also increased the expression of FoxO1 mRNA and reduced renal phosphorylation levels of Akt and FoxO1 protein. These results suggest that liraglutide may exert a renoprotective effect by a FoxO1-mediated upregulation of renal MnSOD expression in the early DKD.