The T-box transcription factor Brachyury promotes renal interstitial fibrosis by repressing E-cadherin expression.
The T-box transcription factor Brachyury promotes renal interstitial fibrosis by repressing E-cadherin expression.
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T-box 转录因子 Brachyury 通过抑制 E-钙粘蛋白表达促进肾间质纤维化。
DOI：
10.1186/s12964-014-0076-4
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发表时间：
2014-11-30
期刊：
影响因子：
--
通讯作者：
Huang C
中科院分区：
文献类型：
--
作者：
Sun S;Sun W;Xia L;Liu L;Du R;He L;Li R;Wang H;Huang C
转化生长因子β 1（TGF-β1）诱导的上皮细胞向间质细胞转化（Epithelial-to-mesenchymal transition，EMT）是肾纤维化的重要因素之一。然而，EMT的潜在分子机制尚未完全了解。Brachyury是一种进化上保守的转录因子，最近被鉴定为促进人类肿瘤细胞系EMT的重要因子。没有证据表明Brachyury参与肾小管EMT。我们的研究结果表明，在TGF-β1处理的人近端肾小管上皮细胞（HK-2）中，Brachyury被显著诱导，并且这种诱导伴随着EMT特征性的变化。在HK-2细胞中通过短干扰RNA（siRNA）阻断Brachyury表达可有效逆转TGF-β1诱导的EMT表型。Brachyury诱导抑制E-钙粘蛋白的转录; E-钙粘蛋白启动子含有Brachyury结合位点，并且当使用启动子用报告构建体转染Brachyury过表达细胞时，E-钙粘蛋白的表达降低。这种作用部分由Slug和Snail介导，因为通过siRNA敲低Snail和Slug有效地逆转了Brachyury介导的EMT并部分恢复了E-钙粘蛋白表达。Brachyury在梗阻性肾病大鼠模型和伊加肾病肾小管间质纤维化组织中也有表达，提示其可能在体内EMT和肾纤维化中起作用。我们的研究结果首次证明Brachyury在调节TGF-β1介导的肾脏EMT中起重要作用，并可能成为肾脏疾病治疗进展的有吸引力的靶点。
Epithelial-to-mesenchymal transition (EMT) induced by TGF-β1 is one of well-recognized factors contributing to renal fibrosis. However, the underlying molecular mechanisms of EMT are not fully understood. Brachyury, an evolutionarily conserved transcription factor, was recently identified as an important factor promoting EMT in human carcinoma cell lines. There is no evidence that Brachyury is involved in renal tubular EMT. Our results demonstrated that Brachyury was prominently induced in TGF-β1-treated human proximal tubular epithelial (HK-2) cells and that this induction was accompanied by changes characteristic of EMT. Blockage of Brachyury expression by short interfering RNA (siRNA) in HK-2 cells effectively reversed the TGF-β1-induced EMT phenotype. Brachyury induction repressed E-cadherin transcription; the E-cadherin promoter contains a Brachyury binding site, and decreased expression of E-cadherin occurred in Brachyury-overexpressing cells when they were transfected with reporter constructs using the promoter. This effect was partially mediated by Slug and Snail, as knockdown of Snail and Slug by siRNA effectively reversed Brachyury-mediated EMT and partially restored E–cadherin expression. The expression of Brachyury also presented in a rat model of obstructive nephropathy and in tubulointerstitial fibrosis tissues of IgA nephropathy, suggesting that it may have a role in EMT and renal fibrosis in vivo. Our results demonstrate for the first time that Brachyury plays an important role in regulating TGF-β1–mediated renal EMT and could be an attractive target for progression of renal disease therapies.
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影响因子：
5.2
作者：
Behr, R;Heneweer, C;Thie, M
通讯作者：
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10.5
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