Liraglutide ameliorates renal injury in streptozotocin-induced diabetic rats by activating endothelial nitric oxide synthase activity via the downregulation of the nuclear factor-κB pathway

Abstract

Accumulating evidence has implicated that liraglutide, one of the human glucagon-like peptide-1 (GLP-1) analogues, elicits protective effects on diabetic nephropathy; however, the mechanism has yet to be fully elucidated. The present study aimed to assess the effect and underlying mechanisms of liraglutide in diabetic nephropathy. Wistar rats with streptozotocin-induced diabetes mellitus were subcutaneously injected with liraglutide or phosphate buffer for 12 weeks at a dose of 0.3 mg/kg/12 h. The biochemical parameters were determined, renal histological examination was performed by hematoxylin and eosin and periodic acid Schiff base staining, and the mRNA levels of nuclear factor κB (NF-κB) and endothelial nitric oxide synthase (eNOS) were assessed by quantitative polymerase chain reaction. Furthermore, the protein expression of NF-κB and eNOS as well as eNOS phosphorylation were examined by western blot analysis and the levels of inflammatory cytokines downstream of NF-κB were evaluated by fluorescence-assisted cell sorting and finally, the eNOS activity and nitric oxide (NO) production were evaluated by ELISA. Liraglutide decreased the levels of total cholesterol, urine, 24-h urinary albumin, blood urea nitrogen, serum creatinine and histological damage. Liraglutide also reduced the expression of NF-κB at mRNA and protein levels; the expression of tumor necrosis factor-α, interferon-γ, interleukin-6 and monocyte chemoattractant protein-1 were also reduced. By contrast, eNOS phosphorylation, eNOS activity and NO production appeared to have increased. Liraglutide may have a direct beneficial effect on diabetic nephropathy by improving eNOS activity by inhibiting the NF-κB pathway without eliciting a glucose lowering effect.