KLF4 Initiates Sustained Activation of YAP After AKI to Promote Renal Fibrosis

Acute renal injury (AKI) has been recognized as long-term risks for progressing into chronic kidney disease (CKD) and interstitial fibrosis. Hippo pathway was previously noticed facilitating the renal tubular repair after AKI. In the ischemia-reperfusion (IR)-induced AKI to CKD animal model, the expression and nucleus distribution of YAP were persistently increased to the end of experiment (21 days after IR surgery). The sustained activation of YAP in post-acute phase of AKI was involved in renal functional decline and interstitial fibrosis. Activation of YAP increased the expression of transforming growth factor-β (TGF-β) and connective tissue growth factor (CTGF). Reprogramming factor KLF4 was lined on the upstream of YAP. KLF4 upregulated the expression of YAP and ITCH. ITCH facilitates YAP activation and nuclear translocation via degrading LATS1. Knockdown on KLF4 attenuated the increase in YAP and nuclear translocation as well as renal functional deterioration and interstitial fibrosis. The expression and nuclear distribution of YAP were also increased in biopsy sample from CKD patients. In conclusion, the activation of YAP in the post-acute phase of AKI is implicated in renal functional deterioration and fibrosis although it exhibits beneficial effect in acute phase. Reprogramming factor KLF4 is responsible for the persistent activation of YAP. Shutting down the activation of KLF4-YAP pathway appropriately might be a way to prevent the transition of AKI into CKD. Funding Statement: This research was financially supported by the Natural Science Foundation of China No. 81873603, 81670664 to Lu L and No. 81770718 to Wang X. Declaration of Interests: All the authors declared no conflict of interests exists. Ethics Approval Statement: All experiments using mice were performed according to the criteria of the Medical Laboratory Animal Administrative Committee of Shanghai and the Guide for Care and Use of Laboratory Animals of Fudan University, and protocols were approved by the Ethics Committee for Experimental Research, Shanghai Medical College, Fudan University