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.

中文翻译：

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肾小管细胞中YAP/KLF5转录级联的激活加重肾损伤

Hippo/YAP 通路在组织稳态中发挥着关键作用。我们之前的工作表明，上游 Hippo 激酶 Mst1 和 Mst2 双敲除 (dKO) 诱导的肾小管 YAP 激活可促进基础条件下的肾小管损伤和肾脏炎症。然而，在受损肾脏中，肾小管 YAP 激活的重要性仍有待确定，因为许多其他损伤途径同时被激活。在这里，我们显示管状 YAP 在单侧输尿管梗阻 (UUO) 后 6 小时已被激活。肾小管YAP缺乏大大减轻了UUO或顺铂引起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，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 的消除所阻断。抑制 KLF5 可防止 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 是肾损伤的关键因素。 YAP 和 KLF5 形成转录级联，其中肾损伤诱导的肾小管 YAP 激活促进 KLF5 转录。该级联的激活会诱导肾小管细胞过度增殖、肾小管损伤和肾脏炎症。