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The role of ubiquitin-proteasome degradation pathway in TGF-β-Smad signaling in kidney diseases

泛素蛋白酶体降解途径在肾脏疾病中 TGF-β-Smad 信号传导中的作用

基本信息

批准号：
15590847
负责人：
YAMAMOTO Tatsuo
金额：
$ 2.24万
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：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590847/
关键词：
ubiquitin Smad TGF-β Smurf kidney fibrosis intracellular signaling

项目摘要

We investigated the levels of Smads that mediate the intracellular TGF-β signaling and the activity of ubiquitin-proteasome degradation directed to Smads in isolated glomeruli from rats with anti-thymocyte serum (ATS) nephritis, a model of mesangial proliferative glomerulonephritis, and mice kidneys receiving unilateral ureteral obstruction (UUO), a model of progressive tubulointerstitial fibrosis. We found the following results.1.Smad2 protein was decreased markedly in ATS nephritic glomeruli and UUO kidneys, while Smad2 mRNA expression did not change in the former and increased in the latter, suggesting the involvement of Smad2-specific degradation mechanism in these lesions.2.Increases in degradation of intrinsic Smad2 protein and ubiquitination activity against Smad2 were noted in ATS nephritic glomeruli and UUO kidneys, and the degradation of Smad2 was blocked by a proteasome inhibitor.3.We cloned the rat Smurf2, an E3 ubiquitin ligase for Smad2.4.Increases in Smurf2 protein and mRNA were noted in ATS nephritic glomeruli and UUO kidneys.5.The decrease of inhibitory Smad7 protein and the enhanced ubiquitination and degradation of Smad7 protein were noted in UUO kidneys, in which the expression of Smad7 mRNA increased.6.The degradation of Smad7 in UUO kidneys was inhibited by a proteasome inhibitor.These data suggest that the increase of the selective ubiquitin-dependent degradation of Smad2 mediated by Smurf2 results in relative predominance of Smad3-mediated TGF-β signaling in ATS nephritic glomeruli and UUO kidneys. The decrease of inhibitory Smad7 resulted from enhanced ubiquitin-dependent degradation may also be involved in the progression of tubulointerstitial fibrosis in UUO kidneys, in which uncontrolled overexpression of TGF-β activity plays a pathogenic role.

我们研究了来自抗胸腺细胞血清（ATS）肾炎大鼠（系膜增生性肾小球肾炎模型）和接受单侧输尿管梗阻（UUO）小鼠肾脏（进行性肾小管间质纤维化模型）的分离肾小球中介导细胞内TGF-β信号传导的Smads水平和针对Smads的泛素-蛋白酶体降解活性。结果表明：1.在ATS肾炎肾小球和UUO肾脏中，Smad 2蛋白表达明显下降，而Smad 2 mRNA表达则明显增加，提示在这些病变中存在Smad 2特异性降解机制; 2.在ATS肾炎肾小球和UUO肾脏中，内源性Smad 2蛋白降解和针对Smad 2的泛素化活性增加，Smad 2的降解被蛋白酶体抑制剂阻断。3.我们克隆了Smad 2的E3泛素连接酶Smurf 2。4.在ATS肾炎肾小球和UUO肾脏中观察到Smurf 2蛋白和mRNA的增加。5.在UUO肾脏中观察到抑制性Smad 7蛋白的减少和Smad 7蛋白的泛素化和降解的增强。6.蛋白酶体抑制剂可抑制UUO肾组织中Smad 7的降解，提示Smurf 2介导的Smad 2选择性泛素依赖性降解的增加导致Smad 3介导的TGF-β 1相对优势，而Smad 7的降解则受到抑制。ATS肾炎肾小球和UUO肾中的β信号传导。由泛素依赖性降解增强引起的抑制性Smad 7的减少也可能参与UUO肾中肾小管间质纤维化的进展，其中TGF-β活性的不受控制的过度表达起致病作用。

项目成果

期刊论文数量（26）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Down-regulation of Smad7 expression by ubiquitin-dependent degradation contributes to renal fibrosis in obstructive nephropathy in mice

DOI：
10.1073/pnas.0400035101
发表时间：
2004-06-08
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
影响因子：
11.1
作者：
Fukasawa, H;Yamamoto, T;Hishida, A
通讯作者：
Hishida, A

Ubiquitin-dependent degradation of Smad2 is increased in the glomeruli of rats with anti-thymocyte serum nephritis.

在患有抗胸腺细胞血清肾炎的大鼠的肾小球中，Smad2 的泛素依赖性降解增加。

DOI：
发表时间：
2003
期刊：
Am.J.Pathol. 163
影响因子：
0
作者：
Chiharu Uchida et al.;Makio Hayakawa et al.;Yasumichi Inoue et al.;Hirotaka Fukasawa et al.;Keiko Nakayama et al.;Mikihiko Naito et al.;Masashi Kimura et al.;Hirotaka Fukasawa et al.;Mikihiko Naito et al.;Hirotaka Fukasawa et al.;Akashi Togawa et al.
通讯作者：
Akashi Togawa et al.

Suzuki H, Yamamoto T, Ikegaya N, Hishida A: "Dietary salt intake modulates progression of anti-thymocyte serum nephritis through alteration of glomerular angiotensin II receptor expression"Am.J.Physiol.. 286・2. F267-F277 (2004)

Suzuki H、Yamamoto T、Ikegaya N、Hishida A：“膳食盐摄入通过改变肾小球血管紧张素 II 受体表达调节抗胸腺细胞血清肾炎的进展”Am.J.Physiol.. 286・2.F267-F277 (2004)