Dipeptidyl peptidase IV inhibitor attenuates kidney injury in streptozotocin-induced diabetic rats.

Abstract

Dipeptidyl peptidase (DPP) IV inhibitors are probably beneficial for preventing diabetic complication and modulating glucagon-like peptide-1 receptor (GLP-1R) expression. The aim of this study was to determine whether the DPP IV inhibitor LAF237 (vildagliptin) has renoprotective qualities in streptozotocin-induced diabetic rats. Diabetic and nondiabetic rats were treated with an oral dose of 4 or 8 mg/kg/day LAF237 or placebo for 24 weeks, and renal injury was observed by light and electron microscopy. We also assessed DPP IV activity, active GLP-1 level, cAMP and 8-hydroxy-deoxyguanosine excretion, and GLP-1R, cleaved caspase 3, and transforming growth factor-β1 (TGF-β1) expression. LAF237 significantly decreased proteinuria, albuminuria, and urinary albumin/creatinine ratio, improved creatinine clearance, and dose-dependently inhibited interstitial expansion, glomerulosclerosis, and the thickening of the glomerular basement membrane in diabetic rats. It is noteworthy that LAF237 markedly down-regulated DPP IV activity and increased active GLP-1 levels, which probably prevented oxidative DNA damage and renal cell apoptosis by activating the GLP-1R and modulating cAMP. Renoprotection was also associated with a reduction in TGF-β1 overexpression. Our study suggests that DPP IV inhibitors may ameliorate diabetic nephropathy as well as reduce the overproduction of TGF-β1. The observed renoprotection is probably attributable to inhibition of DPP IV activity, mimicking of incretin action, and activation of the GLP-1R.

• Authors: Wei Jing Liu, Shu Hua Xie, Yu Ning Liu, Won Kim, Heung Yong Jin, Sung Kwang Park, Yi Ming Shao, Tae Sun Park
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 340 Issue 2 Pg. 248-55 (Feb 2012) ISSN: 1521-0103 [Electronic] United States
• PMID: 22025647 (Publication Type: Journal Article)

Chemical References

• 1-(((3-hydroxy-1-adamantyl)amino)acetyl)-2-cyanopyrrolidine
• Blood Glucose
• Dipeptidyl-Peptidase IV Inhibitors
• Glp1r protein, rat
• Glucagon-Like Peptide-1 Receptor
• Glycated Hemoglobin A
• Insulin
• Pyrrolidines
• Receptors, Glucagon
• Transforming Growth Factor beta1
• 8-Hydroxy-2'-Deoxyguanosine
• Glucagon-Like Peptide 1
• Cyclic AMP
• Dipeptidyl Peptidase 4
• Casp3 protein, rat
• Caspase 3
• Deoxyguanosine
• Adamantane

Topics

• 8-Hydroxy-2'-Deoxyguanosine
• Adamantane (administration & dosage, analogs & derivatives, pharmacology, therapeutic use)
• Animals
• Blood Glucose (drug effects, metabolism)
• Body Weight (drug effects)
• Caspase 3 (metabolism)
• Cyclic AMP (urine)
• Deoxyguanosine (analogs & derivatives, urine)
• Diabetes Mellitus, Experimental (complications, drug therapy, pathology, physiopathology)
• Diabetic Nephropathies (drug therapy, metabolism, pathology, physiopathology)
• Dipeptidyl Peptidase 4 (metabolism)
• Dipeptidyl-Peptidase IV Inhibitors (administration & dosage, pharmacology, therapeutic use)
• Eating (drug effects)
• Gene Expression (drug effects, genetics)
• Glomerular Basement Membrane (drug effects, pathology)
• Glucagon-Like Peptide 1 (blood)
• Glucagon-Like Peptide-1 Receptor
• Glycated Hemoglobin (metabolism)
• Insulin (blood)
• Kidney (drug effects, metabolism, pathology, physiopathology)
• Male
• Pyrrolidines (administration & dosage, pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Receptors, Glucagon (genetics, metabolism)
• Transforming Growth Factor beta1 (metabolism)