Runt-Related Transcription Factor 1 (RUNX1) Promotes TGF-β-Induced Renal Tubular Epithelial-to-Mesenchymal Transition (EMT) and Renal Fibrosis through the PI3K Subunit p110δ.
Runt-Related Transcription Factor 1 (RUNX1) Promotes TGF-β-Induced Renal Tubular Epithelial-to-Mesenchymal Transition (EMT) and Renal Fibrosis through the PI3K Subunit p110δ.
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Runt 相关转录因子 1 (RUNX1) 通过 PI3K 亚基 p110 delta 促进 TGF-β 诱导的肾小管上皮间质转化 (EMT) 和肾纤维化
DOI：
10.1016/j.ebiom.2018.04.023
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发表时间：
2018-05
期刊：
影响因子：
11.1
通讯作者：
Wang H
中科院分区：
文献类型：
--
作者：
Zhou T;Luo M;Cai W;Zhou S;Feng D;Xu C;Wang H
肾纤维化被广泛认为是导致终末期肾衰竭的常见机制。上皮间质转化（EMT）在肾纤维化的发病机制中起重要作用。Runt相关转录因子1（RUNX 1）通过内皮细胞向造血细胞转化（EHT）在造血中起着至关重要的作用，EHT是一个概念上类似于EMT的过程，但其在EMT和肾纤维化中的作用尚不清楚。在这里，我们证明了RUNX 1在TGF-β诱导的部分EMT和肾纤维化过程中过表达，并且RUNX 1的表达水平是SMAD 3依赖性的。RUNX 1的敲除减弱了TGF-β诱导的表型变化和肾小管上皮细胞（RTECs）中EMT标记基因的表达水平。此外，RUNX 1的过表达促进肾小管上皮细胞中EMT标记基因的表达。此外，RUNX 1通过增加PI 3 K亚基p110δ的转录促进TGF-β诱导的部分EMT，所述PI 3 K亚基p110δ介导Akt活化。小鼠RTECs中Runx 1的特异性缺失可减轻单侧输尿管梗阻（UUO）和叶酸（FA）治疗诱导的肾纤维化。这些发现表明RUNX 1是预防肾纤维化的潜在靶点。RUNX 1是TGF-β诱导的肾小管EMT所必需的，其增加Akt活化的p110δ转录。小鼠RTECs中RUNX 1的消融抑制单侧输尿管梗阻或叶酸诱导的肾纤维化。这些发现表明RUNX 1可能被用作预防肾纤维化的潜在靶点。肾纤维化是肾功能衰竭发展过程中的一个重要病理步骤，而上皮细胞向间质细胞转化（EMT）参与了肾纤维化的发病机制。探索新的效应物作为抑制肾纤维化的潜在靶点目前正在进行广泛的研究。本论文已经确定，RUNX 1通过增加PI 3 K亚基p110δ的表达水平和Akt活化而被TGF-β诱导的肾小管EMT所需。重要的是，在小鼠肾小管上皮细胞中消融Runx 1或RUNX 1抑制剂可以减少单侧输尿管梗阻或叶酸治疗下的肾纤维化。这些发现表明，RUNX 1抑制剂可用于预防肾纤维化。
Renal fibrosis is widely considered a common mechanism leading to end-stage renal failure. Epithelial-to-mesenchymal transition (EMT) plays important roles in the pathogenesis of renal fibrosis. Runt-related transcription factor 1(RUNX1) plays a vital role in hematopoiesis via Endothelial-to-Hematopoietic Transition (EHT), a process that is conceptually similar to EMT, but its role in EMT and renal fibrosis is unclear. Here, we demonstrate that RUNX1 is overexpressed in the processes of TGF-β-induced partial EMT and renal fibrosis and that the expression level of RUNX1 is SMAD3-dependent. Knockdown of RUNX1 attenuated both TGF-β-induced phenotypic changes and the expression levels of EMT marker genes in renal tubular epithelial cells (RTECs). In addition, overexpression of RUNX1 promoted the expression of EMT marker genes in renal tubular epithelial cells. Moreover, RUNX1 promoted TGF-β-induced partial EMT by increasing transcription of the PI3K subunit p110δ, which mediated Akt activation. Specific deletion of Runx1 in mouse RTECs attenuated renal fibrosis, which was induced by both unilateral ureteral obstruction (UUO) and folic acid (FA) treatment. These findings suggest that RUNX1 is a potential target for preventing renal fibrosis. RUNX1 is required for TGF-β induced renal tubular EMT, which increases p110δ transcription for Akt activation. Ablation of RUNX1 in mouse RTECs inhibits renal fibrosis induced by unilateral ureteral obstruction or folic acid. These findings suggest that RUNX1 might be used as a potential target to prevent renal fibrosis. Kidney fibrosis is a critical pathologic step during the development of renal failure, while epithelial-to-mesenchymal transition (EMT) contributes to the pathogenesis of renal fibrosis. Exploring the new effectors as potential targets to inhibit renal fibrosis is currently under extensive investigation. This manuscript has identified that RUNX1 is required for TGF-β induced renal tubular EMT via increasing expression levels of the PI3K subunit p110δ and Akt activation. Importantly, ablation of Runx1 in mouse renal tubular epithelial cells or the RUNX1 inhibitor could reduce renal fibrosis in response to unilateral ureteral obstruction or under the treatment of folic acid. These findings suggest that the RUNX1 inhibitor might be used to prevent renal fibrosis.
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作者：
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