Molecular Biological Study for the pathogenesis of glomerulosclerosis

糖尿病肾病是日本和美国终末期肾病的主要病因之一，越来越多的证据表明晚期糖基化终末产物（AGEs）在糖尿病肾小球病变的发展中具有致病作用。我们报道了AGEs与系膜细胞上的特定受体结合，并增加了ECM的合成。利用含有（IV）胶原启动子/增强子和氯霉素乙酰转移酶基因的报告基因构建体进行瞬时转染，测定了AGEs显著提高（IV）胶原基因的转录活性。AGEs还增加了平滑肌α -肌动蛋白mRNA水平及其转录活性。AGEs刺激（IV）胶原基因启动子的核因子结合。此外，AGEs显著降低了（IV）胶原启动子结合蛋白（A1p145）的mRNA水平，A1p145是DNA复制复合体AP1的一个较大亚基。这些结果表明，AGEs通过调节启动子结合蛋白的水平来增加（IV）胶原基因的表达。这些转录事件可能在响应AGEs的ECM积累中起关键作用。

In diabetic nephropathy, one of the major causes of end stage kidney disease in Japan and the United States, there is accumulating evidence that Advanced glycation endproducts (AGEs) have a pathogenic role in the development of diabetic glomerulopathy. We reported that AGEs bound to a specific receptor on mesangial cells and increased synthesis of ECM.AGEs significantly increased transcriptional activity of (IV) collagen gene, measured by transient transfection assays using the reporter gene construct containing (IV) collagen promoter/enhancer and the chloramphericol acetyltransferase gene. AGEs also increased smooth muscle alpha-actin mRNA levels as well as its transcriptional activity. Nuclear factor binding of the promoter of (IV) collagen gene was stimulated by AGEs. Furthermore, AGEs dramatically decreased the mRNA levels of (IV) collagen promoter binding protein (A1p145), a larger subunit of DNA replication complex, AP1. These results suggest that AGEs increase expression of (IV) collagen gene by modulating the levels of promoter binding proteins. These transcriptional events may play a critical role in ECM accumulation in response to AGEs.