Profibrotic epithelial phenotype: a central role for MRTF and TAZ
Profibrotic epithelial phenotype: a central role for MRTF and TAZ
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DOI：
10.1038/s41598-019-40764-7
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发表时间：
2019-03-13
影响因子：
4.6
通讯作者：
Kapus, Andras
中科院分区：
文献类型：
--
作者：
Bialik, Janne Folke;Ding, Mei;Kapus, Andras
上皮损伤是纤维化的关键起始物，但是-与先前的范例相反-原位上皮不经历广泛的上皮-间充质/肌成纤维细胞转化（EMT/EMyT）。相反，它假定以纤维化细胞因子产生为特征的促纤维化上皮表型（PEP）。PEP的转录机制尚未明确。正如我们已经证明的，两个RhoA/细胞因子调节的转录辅激活因子，心肌素相关转录因子（MRTF）和TAZ，是必不可少的EMyT，我们问，如果他们可能介导PEP以及。在这里，我们表明机械应力（循环拉伸）增加了LLC-PK 1肾小管细胞中转化生长因子-β 1（TGF β 1）、结缔组织生长因子（CTGF）、血小板衍生生长因子和印度刺猬mRNA的表达。这些反应通过siRNA介导的沉默或MRTF（CCG-1423）或TAZ（维替泊芬）的药理学抑制而减轻。RhoA抑制发挥类似的作用。单侧输尿管梗阻，一种机械触发的肾纤维化的小鼠模型，诱导肾小管RhoA活化沿着MRTF和TAZ的过表达/核积聚，以及上述细胞因子的转录增加。激光捕获显微切割显示，TAZ，TGF β 1和CTGF诱导特异性在肾小管上皮细胞。CCG-1423抑制这些蛋白质的总肾和肾小管表达。因此，MRTF调节上皮TAZ表达，并且MRTF和TAZ都是PEP相关上皮细胞因子产生的关键介质。
Epithelial injury is a key initiator of fibrosis but - in contrast to the previous paradigm - the epithelium in situ does not undergo wide-spread epithelial-mesenchymal/myofibroblast transition (EMT/EMyT). Instead, it assumes a Profibrotic Epithelial Phenotype (PEP) characterized by fibrogenic cytokine production. The transcriptional mechanisms underlying PEP are undefined. As we have shown that two RhoA/cytoskeleton-regulated transcriptional coactivators, Myocardin-related transcription factor (MRTF) and TAZ, are indispensable for EMyT, we asked if they might mediate PEP as well. Here we show that mechanical stress (cyclic stretch) increased the expression of transforming growth factor-beta 1 (TGF beta 1), connective tissue growth factor (CTGF), platelet-derived growth factor and Indian Hedgehog mRNA in LLC-PK1 tubular cells. These responses were mitigated by siRNA-mediated silencing or pharmacological inhibition of MRTF (CCG-1423) or TAZ (verteporfin). RhoA inhibition exerted similar effects. Unilateral ureteral obstruction, a murine model of mechanically-triggered kidney fibrosis, induced tubular RhoA activation along with overexpression/nuclear accumulation of MRTF and TAZ, and increased transcription of the above-mentioned cytokines. Laser capture microdissection revealed TAZ, TGF beta 1 and CTGF induction specifically in the tubular epithelium. CCG-1423 suppressed total renal and tubular expression of these proteins. Thus, MRTF regulates epithelial TAZ expression, and both MRTF and TAZ are critical mediators of PEP-related epithelial cytokine production.