Down-regulation of Smad7 expression by ubiquitin-dependent degradation contributes to renal fibrosis in obstructive nephropathy in mice
Down-regulation of Smad7 expression by ubiquitin-dependent degradation contributes to renal fibrosis in obstructive nephropathy in mice
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DOI：
10.1073/pnas.0400035101
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发表时间：
2004-06-08
影响因子：
11.1
通讯作者：
Hishida, A
中科院分区：
文献类型：
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作者：
Fukasawa, H;Yamamoto, T;Hishida, A
转化生长因子β (tgf - β)的过度表达已被证明在肾纤维化的进展中起致病作用，小管间质纤维化的严重程度与肾功能的相关性优于肾小球硬化的严重程度。Smad蛋白是tgf - β受体下游的信号转导。已经确定了三个Smad蛋白家族：受体调节的Smad2和Smad3，共同伴侣Smad4和抑制性Smad7（负反馈回路的一部分）。我们研究了smad介导的tgf - β信号通路和Smad7在小鼠单侧输尿管梗阻（UUO）肾脏（进行性小管间质纤维化模型）中的调控机制。与假手术肾脏相比，UUO肾脏中Smad7蛋白水平而非mRNA水平逐渐下降，而核磷酸化Smad2和Smad3的免疫反应性和肾纤维化呈反比增加。此外，我们证明，与假手术肾脏相比，UUO肾脏中Smad7蛋白的降解和泛素化活性均显着增加。我们还发现Smad7的E3泛素连接酶Smurf1和Smurf2 （Smad泛素化调节因子）在UUO肾脏中增加，并且它们与Smad7相互作用。我们的研究结果表明，泛素依赖性降解增强导致Smad7蛋白的减少在小管间质纤维化的进展中起致病作用。
Overexpression of transforming growth factor beta (TGF-beta) has been shown to play pathogenic roles in progression of renal fibrosis, and the severity of tubulointerstitial fibrosis correlates better with renal function than the severity of glomerulosclerosis. Smad proteins are signaling transducers downstream from TGF-beta receptors. Three families of Smad proteins have been identified: receptor-regulated Smad2 and Smad3, common partner Smad4, and inhibitory Smad7 (part of a negative-feed back loop). We investigated Smad-mediated TGF-beta signaling pathway and regulatory mechanisms of inhibitory Smad7 in unilateral ureteral obstruction (UUO) kidneys in mice, a model of progressive tubulointerstitial fibrosis. Compared with sham-operated kidneys, the level of Smad7 protein, but not mRNA, decreased progressively in UUO kidneys, whereas immunoreactivity for nuclear phosphorylated Smad2 and Smad3 and renal fibrosis were inversely increased. Furthermore, we demonstrated that both the degradation and ubiquitination activity of Smad7 protein were increased markedly in UUO kidneys compared with sham-operated ones. We also found that both Smurf1 and Smurf2 (Smad ubiquitination regulatory factors), which are E3 ubiquitin ligases for Smad7, were increased and that they interacted with Smad7 in UUO kidneys. our results suggest that the reduction of Smad7 protein resulting from enhanced ubiquitin-dependent degradation plays a pathogenic role in progression of tubulointerstitial fibrosis.