Molecular Biological Study for the pathogenesis of glomerulosclerosis

肾小球硬化发病机制的分子生物学研究

• 批准号: 05454341
• 负责人: DOI Toshio
• 金额: $ 5.18万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1994
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05454341/
• 关键词: Diabetic Nephropathy; Advanced Glycation; Extracellular Matrix; Collagen IV; Transcription factor; Mesangial cells; Replication

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.

糖尿病肾病是日本和美国终末期肾病的主要原因之一，越来越多的证据表明晚期糖基化终末产物 (AGE) 在糖尿病肾小球病的发展中具有致病作用。我们报道了 AGE 与系膜细胞上的特定受体结合并增加了 ECM 的合成。AGE 显着增加了 (IV) 胶原蛋白基因的转录活性，这是通过使用含有 (IV) 胶原蛋白启动子/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来测量的。 AGE 还增加平滑肌 α-肌动蛋白 mRNA 水平及其转录活性。 (IV) 胶原基因启动子的核因子结合受到 AGE 的刺激。此外，AGE 显着降低了 (IV) 胶原蛋白启动子结合蛋白 (A1p145)（DNA 复制复合物 AP1 的较大亚基）的 mRNA 水平。这些结果表明，AGE 通过调节启动子结合蛋白的水平来增加 (IV) 胶原蛋白基因的表达。这些转录事件可能在响应 AGE 的 ECM 积累中发挥关键作用。

项目成果

Noriyuki Iehara: "Differentiation of smooth muscle phenotypes in mouse mesangial cells" Kidney International. 49. 1330-1341 (1996)

Noriyuki Iehara：“小鼠系膜细胞平滑肌表型的分化”肾脏国际。

komatsu T.kanatsu K.Chi H, kita T.Doi T: "Lipoprotein glomerutopathy with a new apolipoprotein E phenotype" American Journal of kidney Diseases. (in press). (1994)

komatsu T.kanatsu K.Chi H、kita T.Doi T：“具有新载脂蛋白 E 表型的脂蛋白肾病”美国肾脏疾病杂志。

家原 典之: "Advanced glycation end products modulate transcriptional regulation in mesangial cells" Kindney International. 50. 1166-1172 (1996)

Noriyuki Iehara：“高级糖基化终末产物调节系膜细胞的转录调节”Kindney International，50. 1166-1172 (1996)。

土井俊夫: "腎硬化症とメサンギウム細胞-成因における形質変換の役割" 医学のあゆみ. 165. 855 (1993)

Toshio Doi：“肾硬化和系膜细胞 - 转化在发病机制中的作用”医学史 165. 855 (1993)。

田中 誠: "Regulation of apolipoprotein B secretion in hepatocytes from Watanabe heritable hyperlipidemic rabbit,an animal model for familial hypercholesterolemia" Atherosclerosis. 114. 73-82 (1995)

Makoto Tanaka：“渡边遗传性高脂血症兔肝细胞中载脂蛋白 B 分泌的调节，家族性高胆固醇血症的动物模型”动脉粥样硬化。