Renoprotective effect of sitagliptin against hypertensive nephropathy induced by chronic administration of L-NAME in rats: role of GLP-1 and GLP-1 receptor.
The present study was undertaken to assess the possible protective effects of sitagliptin, a dipeptidyl peptidase 4-inhibitor (DPP4), against Nω-nitro-L-arginine methyl ester (L-NAME) induced hypertensive nephropathy in rats. Hypertension was induced in adult rats by administration of L-NAME for 6 weeks. Rats were treated with sitagliptin (10mg/kg/day or 30 mg/kg/day) for six weeks. Chronic L-NAME administration resulted in depletion of serum nitric oxide (NO) associated with elevation in the mean arterial pressure. When compared with the control group; serum urea, serum creatinine, albuminuria, urinary N-acetyl-ß-d-glucosaminidase (NAG) level and renal tissue malondialdhyde (MDA) content were significantly elevated, while creatinine clearance, serum level of glucagon like peptide-1 (GLP-1) as well as renal tissue superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities were signifcantly decreased in L-NAME treated group. Renal expression of mRNA for eNOS and GLP-1 receptors were reduced in the L-NAME treated group as compared with the control group. Treatment with sitagliptin (10mg/kg or 30 mg/kg) successfully ameliorated the deleterious effects of L-NAME on the all tested parameters. Our study indicates a novel protective effect of sitagliptin against L-NAME induced hypertensive nephropathy. An effect which is mediated through, increasing serum level of GLP-1, upregulation of GLP-1 receptors, which in turn, lead to induction of expression eNOS, increased serum NO level, tandem with decreased lipid perodixation and restore the antioxidant defense mechanisms. It is worth mentioning that the effects produced by sitaglipin (30 mg/kg) were superior to the effects obtained by the lower dose.
Department of Clinical Pharmacology, Faculty of Medicine, Zagazig University, Zagazig 4115, Egypt.
Dalia M
DM
Abd El Motteleb
Shimaa M
SM
Elshazly
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D052216:Glucagon-Like Peptide 1 / Q000097:blood*; D000067757:Glucagon-Like Peptide-1 Receptor; D005979:Glutathione Peroxidase / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D006977:Hypertension, Renal / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D009393:Nephritis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000097:blood; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D018027:Receptors, Glucagon / Q000235:genetics*; D000068900:Sitagliptin Phosphate; D013482:Superoxide Dismutase / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use
D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D011719:Pyrazines; D018027:Receptors, Glucagon; D014230:Triazoles; D009569:Nitric Oxide; D052216:Glucagon-Like Peptide 1; D005979:Glutathione Peroxidase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D013482:Superoxide Dismutase; D000068900:Sitagliptin Phosphate; D019331:NG-Nitroarginine Methyl Ester
GLP-1 receptor; L-NAME; MDA; NO; Nephropathy; Sitagliptin