Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan.
Biochem Biophys Res Commun. 2010 Jul 23;398(2):326-30. doi: 10.1016/j.bbrc.2010.06.093. Epub 2010 Jun 26.
There is a growing body of evidence that advanced glycation end products (AGEs) and their receptor (RAGE) interaction evokes oxidative stress generation and subsequently elicits inflammatory and fibrogenic reactions, thereby contributing to the development and progression of diabetic nephropathy. We have previously found that nifedipine, a calcium-channel blocker (CCB), inhibits the AGE-induced mesangial cell damage in vitro. However, effects of nifedipine on proximal tubular cell injury remain unknown. We examined here whether and how nifedipine blocked the AGE-induced tubular cell damage. Nifedipine, but not amlodipine, a control CCB, inhibited the AGE-induced up-regulation of RAGE mRNA levels in tubular cells, which was prevented by the simultaneous treatment of GW9662, an inhibitor of peroxisome proliferator-activated receptor-gamma (PPARgamma). GW9662 treatment alone was found to increase RAGE mRNA levels in tubular cells. Further, nifedipine inhibited the AGE-induced reactive oxygen species generation, NF-kappaB activation and increases in intercellular adhesion molecule-1 and transforming growth factor-beta gene expression in tubular cells, all of which were blocked by GW9662. Our present study provides a unique beneficial aspect of nifedipine on diabetic nephropathy; it could work as an anti-oxidative and anti-inflammatory agent against AGEs in tubular cells by suppressing RAGE expression via PPARgamma activation.
越来越多的证据表明，晚期糖基化终产物（AGEs）及其受体（RAGE）的相互作用会引发氧化应激的产生，并随后引发炎症和纤维化反应，从而促进糖尿病肾病的发生和发展。我们之前发现，硝苯地平是一种钙通道阻滞剂（CCB），可抑制体外AGE 诱导的系膜细胞损伤。然而，硝苯地平对近端肾小管细胞损伤的影响尚不清楚。我们在此研究了硝苯地平是否以及如何阻断 AGE 诱导的肾小管细胞损伤。硝苯地平，但不是氨氯地平，一种对照 CCB，抑制了 AGE 诱导的管状细胞中 RAGE mRNA 水平的上调，而同时用过氧化物酶体增殖物激活受体-γ（PPARγ）抑制剂 GW9662 处理则可阻止这种上调。单独用 GW9662 处理发现可增加管状细胞中 RAGE mRNA 水平。此外，硝苯地平抑制了 AGE 诱导的活性氧生成、NF-κB 激活以及细胞间黏附分子-1 和转化生长因子-β基因表达的增加，所有这些均被 GW9662 阻断。本研究提供了硝苯地平在糖尿病肾病方面的独特有益方面；它可以通过激活 PPARγ抑制 RAGE 表达，作为一种针对 AGEs 的抗氧化和抗炎药物，发挥作用。
