Gli +细胞衍生的成纤维细胞中的Yap / Taz缺失可减轻纤维化。,Journal of the American Society of Nephrology

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Gli +细胞衍生的成纤维细胞中的Yap / Taz缺失可减轻纤维化。
Journal of the American Society of Nephrology ( IF 10.3 ) Pub Date : 2017-08-05 , DOI: 10.1681/asn.2015121354
Ming Liang _{1,

2} , Michael Yu ₂ , Ruohan Xia ₂ , Ke Song ₂ , Jun Wang ₃ , Jinlong Luo ₂ , Guang Chen ₂ , Jizhong Cheng ₄

Affiliation

在受损的肾脏中，增加的细胞外基质（ECM）和组织硬度会通过不完全表征的分子机制刺激肾脏纤维化。转录共激活因子是相关蛋白（Yap）和具有PDZ结合基序的转录共激活因子（Taz）在癌细胞中起机械传感器的作用，并参与肾脏中成纤维细胞的调节。我们假设肾纤维化的发展取决于Yap诱导的肾成纤维细胞的活化和增殖。在小鼠中，单侧输尿管梗阻（UUO）后肾成纤维细胞中Yap表达增加，与间质纤维化恶化有关。在培养的成纤维细胞中，抑制Yap / Taz信号可阻止TGF-β1诱导的成纤维细胞向成肌纤维细胞转化以及ECM产生，而Yap的组成性激活即使在没有TGF-β1的情况下也能促进成纤维细胞转化和ECM产生。而且，在不存在TGF-β1的情况下，在依赖于Yap的活化的过程中，接种在硬化的ECM上的成纤维细胞转化为成肌纤维细胞。在患有UUO的小鼠中，Yap抑制剂韦替泊芬减少了间质纤维化。此外，小鼠中Yap / Taz的Gli1 +细胞特异性敲除抑制了UUO诱导的ECM沉积，成肌纤维细胞积累和间质纤维化。在UUO释放模型中，诱导Gli1 +细胞特异性Yap / Taz基因敲除可部分逆转间质纤维化的发展。因此，在肾脏中，Yap是一种组织机械传感器，可以被ECM激活，并将成纤维细胞转化为成肌纤维细胞。Yap / Taz与ECM的相互作用形成前馈回路，导致肾脏纤维化。确定中断该纤维化周期的机制可能导致抗纤维化治疗的发展。

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Yap/Taz Deletion in Gli+ Cell-Derived Myofibroblasts Attenuates Fibrosis.

In damaged kidneys, increased extracellular matrix (ECM) and tissue stiffness stimulate kidney fibrosis through incompletely characterized molecular mechanisms. The transcriptional coactivators yes-associated protein (Yap) and transcriptional coactivator with PDZ-binding motif (Taz) function as mechanosensors in cancer cells and have been implicated in the regulation of myofibroblasts in the kidney. We hypothesized that the development of kidney fibrosis depends on Yap-induced activation and proliferation of kidney fibroblasts. In mice, Yap expression increased in renal fibroblasts after unilateral ureteral obstruction (UUO), in association with worsening of interstitial fibrosis. In cultured fibroblasts, inhibition of Yap/Taz signaling blocked TGF-β1-induced fibroblast-to-myofibroblast transformation and ECM production, whereas constitutive activation of Yap promoted fibroblast transformation and ECM production even in the absence of TGF-β1. Moreover, in the absence of TGF-β1, fibroblasts seeded on a stiffened ECM transformed into myofibroblasts in a process dependent on the activation of Yap. In mice with UUO, the Yap inhibitor verteporfin reduced interstitial fibrosis. Furthermore, Gli1+ cell-specific knockout of Yap/Taz in mice suppressed UUO-induced ECM deposition, myofibroblast accumulation, and interstitial fibrosis. In a UUO-release model, induction of Gli1+ cell-specific Yap/Taz knockout partially reversed the development of interstitial fibrosis. Thus, in the kidney, Yap is a tissue mechanosensor that can be activated by ECM and transforms fibroblasts into myofibroblasts; the interaction of Yap/Taz and ECM forms a feed-forward loop resulting in kidney fibrosis. Identifying mechanisms that interrupt this profibrotic cycle could lead to the development of anti-fibrosis therapy.

更新日期：2019-11-01

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