Liu Yang, Wang Yu, Xu Chunhua, Zhang Yu, Wang Yang, Qin Jinzhong, Lan Hui-Yao, Wang Li, Huang Yu, Mak Kingston Kinglun, Zheng Zhihua, Xia Yin
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China; Department of Nephrology, Center of Nephrology and Urology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.
Department of Endocrinology and Metabolism, Shenzhen University General Hospital, Shenzhen University, Shenzhen, China.
Mol Ther. 2024 May 1;32(5):1526-1539. doi: 10.1016/j.ymthe.2024.02.031. Epub 2024 Feb 27.
The Hippo/YAP pathway plays a critical role in tissue homeostasis. Our previous work demonstrated that renal tubular YAP activation induced by double knockout (dKO) of the upstream Hippo kinases Mst1 and Mst2 promotes tubular injury and renal inflammation under basal conditions. However, the importance of tubular YAP activation remains to be established in injured kidneys in which many other injurious pathways are simultaneously activated. Here, we show that tubular YAP was already activated 6 h after unilateral ureteral obstruction (UUO). Tubular YAP deficiency greatly attenuated tubular cell overproliferation, tubular injury, and renal inflammation induced by UUO or cisplatin. YAP promoted the transcription of the transcription factor KLF5. Consistent with this, the elevated expression of KLF5 and its target genes in Mst1/2 dKO or UUO kidneys was blocked by ablation of Yap in tubular cells. Inhibition of KLF5 prevented tubular cell overproliferation, tubular injury, and renal inflammation in Mst1/2 dKO kidneys. Therefore, our results demonstrate that tubular YAP is a key player in kidney injury. YAP and KLF5 form a transcriptional cascade, where tubular YAP activation induced by kidney injury promotes KLF5 transcription. Activation of this cascade induces tubular cell overproliferation, tubular injury, and renal inflammation.
河马/Yes相关蛋白（YAP）信号通路在组织稳态中发挥着关键作用。我们之前的研究表明，上游河马激酶Mst1和Mst2双敲除（dKO）诱导的肾小管YAP激活在基础条件下会促进肾小管损伤和肾脏炎症。然而，在许多其他损伤通路同时被激活的受损肾脏中，肾小管YAP激活的重要性仍有待确定。在此，我们发现单侧输尿管梗阻（UUO）6小时后肾小管YAP就已被激活。肾小管YAP缺乏极大地减轻了UUO或顺铂诱导的肾小管细胞过度增殖、肾小管损伤和肾脏炎症。YAP促进转录因子KLF5的转录。与此一致的是，在Mst1/2 dKO或UUO肾脏中KLF5及其靶基因的表达升高被肾小管细胞中Yap的缺失所阻断。抑制KLF5可预防Mst1/2 dKO肾脏中的肾小管细胞过度增殖、肾小管损伤和肾脏炎症。因此，我们的结果表明肾小管YAP是肾脏损伤中的关键因素。YAP和KLF5形成一个转录级联，其中肾脏损伤诱导的肾小管YAP激活促进KLF5转录。该级联的激活诱导肾小管细胞过度增殖、肾小管损伤和肾脏炎症。
