Department of Pediatrics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, China.
Department of Pediatrics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, China; State Key Laboratory of Cell Biology, Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
EBioMedicine. 2018 May;31:217-225. doi: 10.1016/j.ebiom.2018.04.023. Epub 2018 May 11.
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.
肾纤维化被广泛认为是导致终末期肾衰竭的共同机制。上皮-间充质转化（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（RUNX1）在造血过程中通过内皮细胞向造血细胞的转变（EHT）发挥重要作用，这一过程在概念上与 EMT 相似，但它在 EMT 和肾纤维化中的作用尚不清楚。在这里，我们证明 RUNX1 在 TGF-β诱导的部分 EMT 和肾纤维化过程中过度表达，并且 RUNX1 的表达水平依赖于 SMAD3。RUNX1 的敲低减弱了 TGF-β诱导的 RTECs 中表型变化和 EMT 标记基因的表达水平。此外，RUNX1 的过表达促进了肾小管上皮细胞中 EMT 标记基因的表达。此外，RUNX1 通过增加 PI3K 亚基 p110δ的转录来促进 TGF-β诱导的部分 EMT，从而介导 Akt 的激活。在小鼠 RTECs 中特异性敲除 Runx1 可减弱单侧输尿管梗阻（UUO）和叶酸（FA）治疗诱导的肾纤维化。这些发现表明 RUNX1 是预防肾纤维化的潜在靶点。
