sitagliptin-phosphate and Hypertension--Renal

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.

Topics: Animals; Blood Glucose; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glutathione Peroxidase; Hypertension; Hypertension, Renal; Hypoglycemic Agents; Kidney; Lipid Peroxidation; Male; Nephritis; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase Type III; Pyrazines; Rats; Rats, Wistar; Receptors, Glucagon; Sitagliptin Phosphate; Superoxide Dismutase; Triazoles

Dipeptidyl peptidase IV converts neuropeptide Y(1-36) (Y(1)-receptor agonist released from renal sympathetic nerves) to neuropeptide Y(3-36) (selective Y(2)-receptor agonist). Previous studies suggest that Y(1), but not Y(2), receptors enhance renovascular responses to angiotensin II in kidneys from genetically-susceptible animals. Therefore, we hypothesized that inhibition of dipeptidyl peptidase IV with sitagliptin (antidiabetic drug) would augment the ability of exogenous and endogenous neuropeptide Y(1-36) to enhance renal vascular responses to angiotensin II in kidneys from spontaneously hypertensive rats. This hypothesis was tested using 3 protocols in isolated perfused kidneys. Results from Protocol 1: Exogenous neuropeptide Y(1-36) enhanced renovascular responses to angiotensin II. This effect of neuropeptide Y(1-36) was blocked by BIBP3226 (selective Y(1) receptor antagonist); Exogenous neuropeptide Y(3-36) did not enhance renovascular responses to angiotensin II. Results from Protocol 2: Sitagliptin augmented the ability of exogenous neuropeptide Y(1-36) to enhance renovascular responses to angiotensin II. This effect of sitagliptin was blocked by BIBP3226. Results from Protocol 3: Renal sympathetic nerve stimulation enhanced renovascular responses to angiotensin II; this enhancement was augmented by sitagliptin and abolished by BIBP3226. Neuropeptide Y(1-36) via Y(1) receptors enhances renovascular responses to angiotensin II in kidneys from genetically hypertensive animals. Sitagliptin, by blocking dipeptidyl peptidase IV, prevents metabolism of neuropeptide Y(1-36) and thereby increases the effects of neuropeptide Y(1-36) released from renal sympathetic nerves on Y(1) receptors leading to augmentation of neuropeptide Y(1-36)-induced enhancement of the renovascular effects of angiotensin II. The renal effects of dipeptidyl peptidase IV inhibitors in hypertensive diabetic patients merit a closer examination.

Topics: Angiotensin II; Animals; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Drug Synergism; Hypertension, Renal; Kidney; Male; Neuropeptide Y; Peptide Fragments; Pyrazines; Rats; Rats, Inbred SHR; Renal Circulation; Sitagliptin Phosphate; Sympathetic Nervous System; Triazoles; Vasoconstrictor Agents