The transcription factor Twist1 plays a vital role in normal development in many tissue systems and continues to be important throughout life. However, inappropriate Twist1 activity has been associated with kidney injury and fibrosis, though the underlying mechanisms involved remain incomplete. Here, we explored the role of Twist1 in regulating fibroblast behaviors and the development kidney fibrosis. Initially Twist1 protein and activity was found to be markedly increased within interstitial myofibroblasts in fibrotic kidneys in both humans and rodents. Treatment of rat kidney interstitial fibroblasts with transforming growth factor-β1 (a profibrotic factor) also induced Twist1 expression in vitro. Gain- and loss-of-function experiments supported that Twist1 signaling was responsible for transforming growth factor-β1–induced fibroblast activation and fetal bovine serum–induced fibroblast proliferation. Mechanistically, Twist1 protein promoted kidney fibroblast activation by driving the expression of downstream signaling proteins, Prrx1 and Tnc. Twist1 directly enhanced binding to the promoter of Prrx1 but not TNC, whereas the promoter of TNC was directly bound by Prrx1. Finally, mice with fibroblast-specific deletion of Twist1 exhibited less Prrx1 and TNC protein abundance, interstitial extracellular matrix deposition and kidney inflammation in both the unilateral ureteral obstruction and ischemic-reperfusion injury–induced-kidney fibrotic models. Inhibition of Twist1 signaling with Harmine, a β-carboline alkaloid, improved extracellular matrix deposition in both injury models. Thus, our results suggest that Twist1 signaling promotes the activation and proliferation of kidney fibroblasts, contributing to the development of interstitial fibrosis, offering a potential therapeutic target for chronic kidney disease.

中文翻译：

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转录因子 Twist1 通过信号蛋白 Prrx1/TNC 驱动成纤维细胞活化以促进肾纤维化


转录因子 Twist1 在许多组织系统的正常发育中起着至关重要的作用，并且在一生中仍然很重要。然而，不适当的 Twist1 活性与肾损伤和纤维化有关，尽管所涉及的潜在机制仍不完整。在这里，我们探讨了 Twist1 在调节成纤维细胞行为和肾纤维化发展中的作用。最初发现 Twist1 蛋白和活性在人类和啮齿动物纤维化肾的间质肌成纤维细胞中显着增加。用转化生长因子-β1 （一种促纤维化因子） 处理大鼠肾间质成纤维细胞也在体外诱导 Twist1 表达 。获得性和功能丧失实验支持 Twist1 信号转导负责转化生长因子-β1 诱导的成纤维细胞活化和胎牛血清诱导的成纤维细胞增殖。从机制上讲，Twist1 蛋白通过驱动下游信号转导蛋白 Prrx1 和 Tnc 的表达来促进肾成纤维细胞活化。Twist1 直接增强与 Prrx1 启动子的结合，而不是 TNC，而 TNC 的启动子直接与 Prrx1 结合。最后，在单侧输尿管梗阻和缺血再灌注损伤诱导的肾纤维化模型中，Twist1 成纤维细胞特异性缺失的小鼠表现出较少的 Prrx1 和 TNC 蛋白丰度、间质细胞外基质沉积和肾脏炎症。Harmine（一种 β-咔啉生物碱）抑制 Twist1 信号传导，改善了两种损伤模型中的细胞外基质沉积。 因此，我们的结果表明，Twist1 信号传导促进肾成纤维细胞的激活和增殖，促进间质纤维化的发展，为慢性肾病提供潜在的治疗靶点。