Influence of Dipeptidyl Peptidase-IV Inhibitor Sitagliptin on Extracellular Signal-Regulated Kinases 1/2 Signaling in Rats with Diabetic Nephropathy.
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.
Department of Nephrology, Shanxi Dayi Hospital (Shanxi Academy of Medical Sciences), Taiyuan, China.
Xiaojun
X
Ren
Gaohong
G
Liu
Yanhong
Y
Wang
Wan
W
Zhang
Fuping
F
Xue
Rongshan
R
Li
Weimin
W
Yu
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D003928:Diabetic Nephropathies / Q000503:physiopathology / Q000517:prevention & control*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D000068900:Sitagliptin Phosphate / Q000008:administration & dosage / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D016212:Transforming Growth Factor beta; D052216:Glucagon-Like Peptide 1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000068900:Sitagliptin Phosphate
Diabetic nephropathy; Extracellular signal-regulated kinases 1/2; Glucagon-like peptide-1; Podocyte; Sitagliptin