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 glucagonlike 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-␤1 (TGF-␤1) 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-␤1 overexpression. Our study suggests that DPP IV inhibitors may ameliorate diabetic nephropathy as well as reduce the overproduction of TGF-␤1. The observed renoprotection is probably attributable to inhibition of DPP IV activity, mimicking of incretin action, and activation of the GLP-1R.

Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction

“…Our findings agree with those of previous studies, which demonstrated DPPIV inhibition to protect the kidney against ischemia-reperfusion injury animal models of type 1 and type 2 diabetic nephropathy. [18][19][20][21] It has been proposed that the protective effects of DPPIV inhibition are mediated by increased circulating levels of GLP-1. 17,20 In our study, we used a model of kidney injury to simulate progressive tubulointerstitial fibrosis and elucidate the effects of DPPIV inhibition independent of GLP-1.…”

Autophagy-Lysosome Pathway in Renal Tubular Epithelial Cells Is Disrupted by Advanced Glycation End Products in Diabetic Nephropathy

“…Immunofluorescence Study-An immunostaining analysis of the tissues and cells was performed as described previously (15).…”

DA-1229, a dipeptidyl peptidase IV inhibitor, protects against renal injury by preventing podocyte damage in an animal model of progressive renal injury

“…13,14,34 These studies found that DPPIV inhibition led to reduced albuminuria and histological damage; these effects were associated with anti-inflammatory and antioxidant properties. However, it is difficult to determine whether the renal effects of DPPIV inhibitors are independent of their glucose-lowering effects.…”

“…[1][2][3][4][5][6] Many experimental and clinical trials have concluded that DPPIV inhibition decreases albuminuria in DN and can potentially delay the onset and progression of DN, in addition to improving kidney function in glycemic controls. [7][8][9][10][11][12][13][14] Numerous studies have provided evidence that podocyte dysfunction, such as podocyte loss, has a central role in the development and progression of DN. 15,16 For example, the decreased nephrin expression observed in DN has been associated with increased albuminuria, and recent reports have also demonstrated that DPPIV expression is upregulated in the glomeruli of patients with DN.…”