Bromodomain-containing protein 4 contributes to renal fibrosis through the induction of epithelial-mesenchymal transition
Bromodomain-containing protein 4 contributes to renal fibrosis through the induction of epithelial-mesenchymal transition
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含溴结构域蛋白 4 通过诱导上皮间质转化促进肾纤维化
DOI：
10.1016/j.yexcr.2019.111507
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发表时间：
2019
影响因子：
3.7
通讯作者：
Zhang Weiru
中科院分区：
文献类型：
--
作者：
Wang Xuan;Zhou Yueyuan;Peng Yi;Huang Ting;Xia Fan;Yang Tianlun;Duan Qiong;Zhang Weiru
纤维化是肾脏疾病的常见病理。高血压肾病（HN）是最常见的继发性肾病之一，通常进展为严重的肾纤维化，除了控制高血压外，治疗选择有限。含溴结构域蛋白4（Brd 4）最近被认为是炎症性疾病和肿瘤病理基础的信号通路中的靶点。最近开发的Brd 4抑制剂JQ 1已被证明具有抗纤维化作用，并正在临床上探索作为抗炎和抗肿瘤药物。在这里，使用人肾活检和血管紧张素II诱导的小鼠纤维化肾脏样本，我们表明，Brd 4在HN患者和高血压小鼠模型的肾组织中上调。在小鼠中，JQ 1减轻血管紧张素II诱导的肾纤维化，并通过改变上皮-间质转化（EMT）相关蛋白的表达来阻断EMT。使用暴露于血管紧张素II的HK 2细胞的体外模型，我们还证明了JQ 1抑制这些细胞中纤维化基因的蛋白质表达。这些结果进一步暗示Brd 4在HN的纤维化反应中，并揭示Brd 4是潜在的抗纤维化靶点。BET抑制剂目前正在临床试验中作为抗肿瘤剂进行研究，并显示出有效的药理作用。我们的研究结果表明，BET抑制剂也可能是HN的潜在转化疗法。
Fibrosis is a common pathology in renal disease. Hypertensive nephropathy (HN) is one of the most common secondary nephropathies that often progresses to severe renal fibrosis with limited treatment options beyond hypertension control. Bromodomain-containing protein 4 (Brd4) was recently recognized as a target in signaling pathways that underlie the pathologies of inflammatory diseases and tumors. A recently developed inhibitor of Brd4, JQ1, has been shown to exert antifibrotic effects and is being clinically explored as an anti-inflammatory and antitumor drug. Here, using human kidney biopsies and Angiotensin II-induced mouse fibrotic kidney samples, we show that Brd4 was upregulated in renal tissue from HN patients and hypertensive mouse models. In mice, JQ1 alleviated Angiotensin II-induced kidney fibrosis and blocked epithelial-mesenchymal transition (EMT) by altering the expression of EMT-related proteins. Using anin vitromodel of HK2 cells exposed to Angiotensin II, we also demonstrated that JQ1 suppressed the protein expression of fibrotic genes in these cells. These results further implicate Brd4 in the fibrotic response in HN and reveal that Brd4 is a potential antifibrotic target. BET inhibitors are currently being investigated in clinical trials as antitumor agents and show potent pharmacological effects. Our findings suggest that BET inhibitors may also be potential translational therapies for HN.