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Cell proliferation, matrix production, and Smad-mediated intracellular TGF-β signaling in glomerulonephritis

肾小球肾炎中的细胞增殖、基质产生和 Smad 介导的细胞内 TGF-β 信号传导

基本信息

批准号：
12671035
负责人：
YAMAMOTO Tatsuo
金额：
$ 2.43万
依托单位：
Hamamatsu University School of Medicine
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 2002
项目状态：
已结题

项目摘要

We investigated the changes of Smad-mediated intracellular TGF-β signaling in glomeruli of rats with anti-thymocyte serum (ATS) nephritis, in which glomeruli show transient increase of TGF-β1 expression and matrix deposition, and found the following results.1. Smad2 protein decreased markedly in ATS nephritic glomeruli, while no significant changes were noted in the levels of Smad3 and Smad4 proteins.2. No significant changes were noted in glomerular expression of Smad2 mRNA, suggesting that the decrease of Smad2 protein was not due to decreased gene expression, but to regulated degradation of Smad2 protein.3. Degradation of endogenous Smad2 protein increased remarkably in ATS nephritic glomeruli.4. Ubiquitination of exogenous recombinant Smad2 increased in the glomerular extracts obtained from rats with ATS nephritis.5. Expression of Smurf2, an E3 ubiquitin ligase for Smad2, increased in ATS nephritic glomeruli.6. The number of glomerular nuclei positive for Smad3 increased in ATS nephritic glomeruli, suggesting that Smad3-mediated TGF-β signaling worked in ATS nephritic glomeruli.These data suggest that the decrease of Smad2 resulted from enhanced ubiquitin-dependent degradation of Smad2 mediated by Smurf2 is involved in the regulation of Smad2-mediated TGF-β signaling in ATS nephritic glomeruli. Increase of the selective degradation of Smad2 may cause relative predominance of Smad3-mediated TGF-β signaling in ATS nephritic glomeruli.

本研究观察了抗胸腺细胞血清（ATS）肾炎大鼠肾小球TGF-β1表达一过性增高和基质沉积时，Smad介导的细胞内TGF-β信号通路的变化，结果发现：1. ATS肾炎肾小球Smad 2蛋白表达明显降低，而Smad 3和Smad 4蛋白表达无明显变化.肾小球Smad 2 mRNA表达无明显变化，提示Smad 2蛋白表达的降低不是由于基因表达的降低，而是由于Smad 2蛋白降解的调节.内源性Smad 2蛋白的降解在ATS肾炎肾小球中显著增加.外源性重组Smad 2在ATS肾炎大鼠肾小球提取物中的泛素化增加. Smurf 2（Smad 2的E3泛素连接酶）的表达在ATS肾炎肾小球中增加。结果表明，Smad 3阳性的肾小球细胞核数目增多，提示Smad 3介导的TGF-β信号通路在ATS肾小球中起作用，提示Smad 2的减少可能与Smad 2介导的TGF-β信号通路的调节有关。Smad 2选择性降解增加可能导致ATS肾炎肾小球中Smad 3介导的TGF-β信号相对优势。