Abstract
Dipeptidyl peptidase (DPP) IV inhibitors are likely beneficial for treating diabetic complication and modulating glucagon-like peptide-1 receptor (GLP-1R) expression. The aim of this study was to determine if the DPP IV inhibitor, LAF237, has renoprotective qualities in streptozotocin-induced diabetic rats. Diabetic and non-diabetic rats were treated with an oral dose of 4 or 8mg/kg/day LAF237 or placebo for 24 weeks, and renal injury was observed by light and electron microscopy. We also assessed DPP IV activity, GLP-1 level, cAMP and 8-OhdG excretion, and GLP-1R, caspase 3 and transforming growth factor (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. Notably, LAF237 markedly down-regulated DPP IV activity and increased GLP-1 levels, which likely 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 incretin action and activating the GLP-1R.
- Received August 11, 2011.
- Revision received October 20, 2011.
- Accepted October 21, 2011.
- The American Society for Pharmacology and Experimental Therapeutics