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.
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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)
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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
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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)
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