PT  - JOURNAL ARTICLE
AU  - Liu, Wei Jing
AU  - Xie, Shu Hua
AU  - Liu, Yu Ning
AU  - Kim, Won
AU  - Jin, Heung Yong
AU  - Park, Sung Kwang
AU  - Shao, Yi Ming
AU  - Park, Tae Sun
TI  - Dipeptidyl Peptidase IV Inhibitor Attenuates Kidney Injury in Streptozotocin-Induced Diabetic Rats
AID  - 10.1124/jpet.111.186866
DP  - 2012 Feb 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 248--255
VI  - 340
IP  - 2
4099  - http://jpet.aspetjournals.org/content/340/2/248.short
4100  - http://jpet.aspetjournals.org/content/340/2/248.full
SO  - J Pharmacol Exp Ther2012 Feb 01; 340
AB  - 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.