Influence of Dipeptidyl Peptidase-IV Inhibitor Sitagliptin on Extracellular Signal-Regulated Kinases 1/2 Signaling in Rats with Diabetic Nephropathy

Abstract

The protective effects of sitagliptin on the kidneys of rats with diabetic nephropathy (DN) and its influence on extracellular signal-regulated kinases 1/2 (ERK1/2) signaling were investigated. Male Wistar rats (n = 40) were randomly assigned to normal control, DN, low-dose sitagliptin intervention (ST1), or high-dose sitagliptin intervention (ST2) groups. Animals were euthanized after a 16-week treatment, and blood glucose (BG), glycosylated hemoglobin (HbA1c), urinary albumin excretion rate (AER), serum creatinine (Scr), creatinine clearance rate (Ccr), active glucagon-like peptide-1 (GLP-1) levels, kidney hypertrophy index, and renal pathohistology were determined. Immunohistochemical methods and real-time polymerase chain reaction (PCR) were used to detect protein and mRNA expression of podocalyxin, ERK1/2, GLP-1 receptor (GLP-1R) and transforming growth factor-β (TGF-β). After 16 weeks, BG, AER, Scr, HbA1c and the kidney hypertrophy index were all significantly decreased (p < 0.05) in ST1 and ST2 groups, while Ccr and active GLP-1 levels were increased (p < 0.05), with changes more pronounced in ST2 (p < 0.05). Glomerular pathological lesions were also improved following sitagliptin treatment, especially in ST2. Immunohistochemical and real-time PCR revealed that protein and mRNA expression levels of podocalyxin and GLP-1R were increased significantly in ST1 and ST2, while expression of ERK1/2 and TGF-β was decreased (p < 0.05). Sitagliptin therefore delayed DN progression, possibly via the inhibition of ERK1/2 signaling and promotion of the interaction between GLP-1 and the GLP-1R.