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Basic approach for intervention of renal sclerosis by modulating apoptosis

调控细胞凋亡干预肾硬化的基本途径

基本信息

批准号：
12670096
负责人：
HISHIKAWA Keiichi
金额：
$ 2.11万
依托单位：
TEIKYO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670096/
关键词：
apoptosis micro array CTGF caspase caspase

项目摘要

Connective tissue growth factor (CTGF) is overexpressed in a variety of fibrotic disorders such as renal fibrosis and atherosclerosis. Fibrosis is a common final pathway of renal diseases of diverse etiology, including inflammation, hemodynamics, and metabolic injury. Mechanical strains such as stretch, shear stress and static pressure are possible regulatory elements in CTGF expression. In this study, we examined the ability of static pressure to modulate CTGF gene expression in cultured human mesangial cells. Low static pressure (40-80 mmHg) stimulated cell proliferation via a protein kinase C dependent pathway. In contrast high static pressure (100-180 mmHg) induced apoptosis in human mesangial cells. This effect was reversed by treatment with CTGF antisense oligonucleotide, but not with transforming growth factor β(TGF-β1) neutralizing antibody or protein kinase C inhibitor. High static pressure not only up-regulated the expression of CTGF, but also the expression of extracellular matrix proteins (collagen I and IV, laminin). This up-regulation of extracellular matrix proteins was also reversed by treatment with CTGF antisense oligonucleotide. As judged by mRNA expression of a total of 1100 genes including apoptosis associated genes using DNA microarray techniques, recombinant CTGF protein induced apoptosis by down-regulation of a number of anti-apoptotic genes. Overexpression of CTGF in mesangial cells by transient transfection had similar effects Taken together, these results suggest that high blood pressure up-regulates CTGF expression in mesangial cells. High levels of CTGF in turn enhance extracellular matrix production and induce apoptosis in mesangial cells, and may contribute to remodeling of mesangium and ultimately glomerulosclerosis.

结缔组织生长因子（CTGF）在多种纤维化疾病如肾纤维化和动脉粥样硬化中过表达。纤维化是多种病因的肾脏疾病的常见最终途径，包括炎症、血流动力学和代谢损伤。机械应力如拉伸、剪切应力和静压是CTGF表达的可能调控元件。在这项研究中，我们研究的能力，静态压力调节CTGF基因表达在培养的人肾小球系膜细胞。低静压（40-80 mmHg）通过蛋白激酶C依赖性途径刺激细胞增殖。相反，高静压（100-180毫米汞柱）诱导人肾小球系膜细胞凋亡。CTGF反义寡核苷酸可逆转这种作用，而转化生长因子β 1（TGF-β1）中和抗体或蛋白激酶C抑制剂则不能逆转这种作用。高静压力不仅上调CTGF的表达，而且还上调细胞外基质蛋白（胶原I和IV，层粘连蛋白）的表达。这种细胞外基质蛋白的上调也被CTGF反义寡核苷酸逆转。如使用DNA微阵列技术通过包括凋亡相关基因在内的总共1100个基因的mRNA表达所判断的，重组CTGF蛋白通过下调许多抗凋亡基因来诱导凋亡。通过瞬时转染在系膜细胞中CTGF过表达具有类似的效果。总之，这些结果表明高血压上调了系膜细胞中CTGF的表达。高水平的CTGF反过来又增强细胞外基质的产生并诱导系膜细胞凋亡，并可能有助于系膜重塑并最终导致肾小球硬化。