Dipeptidyl Peptidase IV Inhibitor Attenuates Kidney Injury in Streptozotocin-Induced Diabetic Rats
Dipeptidyl Peptidase IV Inhibitor Attenuates Kidney Injury in Streptozotocin-Induced Diabetic Rats
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DOI：
10.1124/jpet.111.186866
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发表时间：
2012-02-01
影响因子：
3.5
通讯作者：
Park, Tae Sun
中科院分区：
文献类型：
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作者：
Liu, Wei Jing;Xie, Shu Hua;Park, Tae Sun
二肽基肽酶（DPP）IV抑制剂可能有助于预防糖尿病并发症和调节胰高血糖素样肽-1受体（GLP-1 R）表达。本研究的目的是确定DPP IV抑制剂LAF 237（vildagelatin）是否具有链脲佐菌素诱导的糖尿病大鼠的肾脏保护作用。糖尿病和非糖尿病大鼠用4或8 mg/kg/天的LAF 237或安慰剂口服剂量治疗24周，并通过光学和电子显微镜观察肾损伤。我们还评估了DPP IV活性、活性GLP-1水平、cAMP和8-羟基-脱氧鸟苷排泄以及GLP-1 R、裂解半胱天冬酶3和转化生长因子-β 1（TGF-β 1）表达。LAF 237显著降低糖尿病大鼠的蛋白尿、白蛋白尿和尿白蛋白/肌酐比值，改善肌酐清除率，并剂量依赖性地抑制间质扩张、肾小球硬化和肾小球基底膜增厚。值得注意的是，LAF 237显著下调DPP IV活性并增加活性GLP-1水平，这可能通过激活GLP-1 R和调节cAMP来防止氧化性DNA损伤和肾细胞凋亡。肾保护也与TGF-β 1过度表达的减少有关。我们的研究表明，DPP IV抑制剂可以改善糖尿病肾病以及减少TGF-β 1的过度产生。观察到的肾保护作用可能归因于DPP IV活性抑制、肠促胰岛素作用模拟和GLP-1 R激活。
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-beta 1 (TGF-beta 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-beta 1 overexpression. Our study suggests that DPP IV inhibitors may ameliorate diabetic nephropathy as well as reduce the overproduction of TGF-beta 1. The observed renoprotection is probably attributable to inhibition of DPP IV activity, mimicking of incretin action, and activation of the GLP-1R.