Hypoxia-induced Bmi1 promotes renal tubular epithelial cell-mesenchymal transition and renal fibrosis via PI3K/Akt signal.
Hypoxia-induced Bmi1 promotes renal tubular epithelial cell-mesenchymal transition and renal fibrosis via PI3K/Akt signal.
复制标题
缺氧诱导的 Bmi1 通过 PI3K/Akt 信号促进肾小管上皮细胞间质转化和肾纤维化。
DOI：
10.1091/mbc.e14-01-0044
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发表时间：
2014-09-01
影响因子：
3.3
通讯作者：
Sun S
中科院分区：
文献类型：
--
作者：
Du R;Xia L;Ning X;Liu L;Sun W;Huang C;Wang H;Sun S
体外和体内研究表明，肾上皮细胞中HIF-1a/Twist-Bmi 1信号通路的激活与慢性肾脏疾病的发生有关，并可能通过调节PI 3 K/Akt/Snail信号通路促进EMT而促进纤维化。缺氧是肾纤维化发生发展的重要微环境因素，但其机制尚不清楚。在这里，我们表明，缺氧诱导人肾小管上皮细胞Bmi 1 mRNA和蛋白质的表达。我们进一步证明，Bmi 1的表达可能直接调节低氧诱导因子-1a（HIF-1a）在低氧下。此外，染色质免疫沉淀和报告基因分析研究表明，Bmi 1的协同转录由HIF-1α和Twist。Bmi-1表达增强可诱导上皮-间充质转化（EMT），而内源性Bmi-1表达沉默可逆转缺氧诱导的EMT。Bmi 1的上调通过调节PI 3 K/Akt信号通路导致Snail的稳定，而PI 3 K/Akt信号通路的阻断部分地挽救了Bmi 1过表达细胞的表型，表明PI 3 K/Akt信号通路可能是Bmi 1诱导EMT的主要介质。在梗阻性肾病大鼠模型中，Bmi 1表达以时间依赖性方式增加。此外，我们证明了与HIF-1α和Twist相关的Bmi 1水平升高与慢性肾脏疾病患者相关。我们提供的体外和体内证据表明，肾上皮细胞中HIF-1a/Twist-Bmi 1信号的激活与慢性肾脏疾病的发展相关，并可能通过促进EMT调节PI 3 K/Akt/Snail信号来促进纤维化。
In vitro and in vivo evidence shows that activation of HIF-1a/Twist-Bmi1 signaling in renal epithelial cells is associated with the development of chronic renal disease and may promote fibrogenesis via modulation of PI3K/Akt/Snail signaling by facilitating EMT. Hypoxia is an important microenvironmental factor in the development of renal fibrosis; however, the underlying mechanisms are not well elucidated. Here we show that hypoxia induces Bmi1 mRNA and protein expression in human tubular epithelial cells. We further demonstrate that Bmi1 expression might be directly regulated by hypoxia-inducible factor-1a (HIF-1a) under low oxygen. Moreover, chromatin immunoprecipitation and reporter gene assay studies reveal cooperative transactivation of Bmi1 by HIF-1α and Twist. Enforced Bmi1 expression induces epithelial–mesenchymal transition (EMT), whereas silencing endogenous Bmi-1 expression reverses hypoxia-induced EMT. Up-regulation of Bmi1 leads to stabilization of Snail via modulation of PI3K/Akt signaling, whereas ablation of PI3K/Akt signaling partially rescues the phenotype of Bmi1-overexpressing cells, indicating that PI3K/Akt signaling might be a major mediator of Bmi1-induced EMT. In a rat model of obstructive nephropathy, Bmi1 expression increases in a time-dependent manner. Furthermore, we demonstrate that increased levels of Bmi1, correlated with HIF-1α and Twist, are associated with patients with chronic kidney disease. We provide in vitro and in vivo evidence that activation of HIF-1a/Twist-Bmi1 signaling in renal epithelial cells is associated with the development of chronic renal disease and may promote fibrogenesis via modulation of PI3K/Akt/Snail signaling by facilitating EMT.