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.
MeSH terms
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8-Hydroxy-2'-Deoxyguanosine
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Adamantane / administration & dosage
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Adamantane / analogs & derivatives
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Adamantane / pharmacology
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Adamantane / therapeutic use
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Animals
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Blood Glucose / drug effects
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Blood Glucose / metabolism
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Body Weight / drug effects
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Caspase 3 / metabolism
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Cyclic AMP / urine
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Deoxyguanosine / analogs & derivatives
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Deoxyguanosine / urine
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Diabetes Mellitus, Experimental / complications*
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Diabetes Mellitus, Experimental / drug therapy*
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Diabetes Mellitus, Experimental / pathology
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Diabetes Mellitus, Experimental / physiopathology
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Diabetic Nephropathies / drug therapy*
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Diabetic Nephropathies / metabolism
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Diabetic Nephropathies / pathology
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Diabetic Nephropathies / physiopathology
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Dipeptidyl Peptidase 4 / metabolism
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Dipeptidyl-Peptidase IV Inhibitors / administration & dosage
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Dipeptidyl-Peptidase IV Inhibitors / pharmacology
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Dipeptidyl-Peptidase IV Inhibitors / therapeutic use*
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Eating / drug effects
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Gene Expression / drug effects
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Gene Expression / genetics
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Glomerular Basement Membrane / drug effects
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Glomerular Basement Membrane / pathology
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Glucagon-Like Peptide 1 / blood
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Glucagon-Like Peptide-1 Receptor
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Glycated Hemoglobin / metabolism
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Insulin / blood
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Kidney / drug effects
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Kidney / metabolism
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Kidney / pathology
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Kidney / physiopathology
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Male
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Pyrrolidines / administration & dosage
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Pyrrolidines / pharmacology
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Pyrrolidines / therapeutic use
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Rats
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Rats, Sprague-Dawley
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Receptors, Glucagon / genetics
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Receptors, Glucagon / metabolism
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Transforming Growth Factor beta1 / metabolism
Substances
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1-(((3-hydroxy-1-adamantyl)amino)acetyl)-2-cyanopyrrolidine
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Blood Glucose
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Dipeptidyl-Peptidase IV Inhibitors
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Glp1r protein, rat
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Glucagon-Like Peptide-1 Receptor
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Glycated Hemoglobin A
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Insulin
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Pyrrolidines
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Receptors, Glucagon
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Transforming Growth Factor beta1
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8-Hydroxy-2'-Deoxyguanosine
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Glucagon-Like Peptide 1
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Cyclic AMP
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Dipeptidyl Peptidase 4
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Casp3 protein, rat
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Caspase 3
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Deoxyguanosine
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Adamantane