Background Increasing evidence indicates that renal recovery from AKI stems from dedifferentiation and proliferation of surviving tubule epithelial cells. Both EGF receptor (EGFR) and the Hippo signaling pathway are implicated in cell proliferation and differentiation, and previous studies showed that activation of EGFR in renal proximal tubule epithelial cells (RPTCs) plays a critical role in recovery from ischemia-reperfusion injury (IRI). In this study, we explored RPTC activation of Yes-associated protein (YAP) and transcriptional coactivator with PDZ binding motif (TAZ), two key downstream effectors of the Hippo pathway, and their potential involvement in recovery from AKI.

Methods We used immunofluorescence to examine YAP expression in kidney biopsy samples from patients with clinical AKI and controls (patients with minimal change disease). Studies of RPTC activation of YAP and TAZ used cultured human RPTCs that were exposed to hypoxia-reoxygenation as well as knockout mice (with inducible deletions of Yap, Taz, or both occurring specifically in RPTCs) that were subjected to bilateral IRI.

Results YAP was activated in RPTCs in kidneys from post-AKI patients and post-IRI mouse kidneys. Inhibition of the interaction of YAP and the TEA domain (TEAD) transcription factor complex by verteporfin or conditional deletion of YAP in RPTCs delayed renal functional and structural recovery from IRI, whereas TAZ deletion had no effect. Activation of the EGFR-PI3K-Akt pathway in response to IRI signaled YAP activation, which promoted cell cycle progression.

Conclusions This study shows that EGFR-PI3K-Akt–dependent YAP activation plays an essential role in mediating epithelial cell regeneration during kidney recovery from AKI.

背景技术越来越多的证据表明，从AKI肾恢复源自存活的肾小管上皮细胞的去分化和增殖。EGF受体（EGFR）和Hippo信号通路均参与细胞增殖和分化，并且先前的研究表明，肾近端小管上皮细胞（RPTC）中EGFR的激活在缺血再灌注损伤（IRI）的恢复中起关键作用。在这项研究中，我们探讨了RPTC激活Yes相关蛋白（YAP）和具有PDZ结合基序（TAZ）的转录共激活因子（河马途径的两个关键下游效应子）及其在从AKI恢复中的潜在参与。

方法我们使用免疫荧光法检查了临床AKI患者和对照组（病情极轻的患者）的肾脏活检样本中YAP的表达。对YAP和TAZ的RPTC激活的研究使用了暴露于低氧-复氧的培养的人类RPTC以及敲除小鼠（在RPTC中诱导诱导的Yap和Taz缺失，或两者均特异发生），接受了双边IRI。

结果AAP后患者肾脏和IRI后小鼠肾脏的RPTC中的YAP被激活。Verteporfin抑制RAP中YAP和TEA域（TEAD）转录因子复合物的相互作用或在RPTC中有条件地删除YAP延迟了IRI的肾功能和结构恢复，而TAZ删除则没有作用。响应IRI，EGFR-PI3K-Akt途径的激活表明YAP激活，从而促进细胞周期进程。

结论这项研究表明，依赖EGFR-PI3K-Akt的YAP激活在AKI肾脏恢复过程中在介导上皮细胞再生中起重要作用。