14-3-3ζ inhibits maladaptive repair in renal tubules by regulating YAP and reduces renal interstitial fibrosis

Tian-tian Wang1, Ling-ling Wu1, Jie Wu1, Li-sheng Zhang2, Wan-jun Shen1, Ying-hua Zhao1, Jiao-na Liu1, Bo Fu1, Xu Wang1, Qing-gang Li1, Xue-yuan Bai1, Li-qiang Wang3, Xiang-mei Chen1
1 Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People’s Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing 100853, China
2 College of Veterinary Medicine/College of Biomedicine and Health, Huazhong Agricultural University, Wuhan 430070, China
3 Department of Ophthalmology, Chinese PLA General Hospital, Beijing 100853, China
Correspondence to: Li-qiang Wang:, Xiang-mei Chen:,
DOI: 10.1038/s41401-022-00946-y
Received: 7 February 2022
Accepted: 30 May 2022
Advance online: 15 July 2022


Acute kidney injury (AKI) refers to a group of common clinical syndromes characterized by acute renal dysfunction, which may lead to chronic kidney disease (CKD), and this process is called the AKI-CKD transition. The transcriptional coactivator YAP can promote the AKI-CKD transition by regulating the expression of profibrotic factors, and 14-3-3 protein zeta (14-3-3ζ), an important regulatory protein of YAP, may prevent the AKI-CKD transition. We established an AKI-CKD model in mice by unilateral renal ischemia- reperfusion injury and overexpressed 14-3-3ζ in mice using a fluid dynamics-based gene transfection technique. We also overexpressed and knocked down 14-3-3ζ in vitro. In AKI-CKD model mice, 14-3-3ζ expression was significantly increased at the AKI stage. During the development of chronic disease, the expression of 14-3-3ζ tended to decrease, whereas active YAP was consistently overexpressed. In vitro, we found that 14-3-3ζ can combine with YAP, promote the phosphorylation of YAP, inhibit YAP nuclear translocation, and reduce the expression of fibrosis-related proteins. In an in vivo intervention experiment, we found that the overexpression of 14-3-3ζ slowed the process of renal fibrosis in a mouse model of AKI-CKD. These findings suggest that 14-3-3ζ can affect the expression of fibrosis-related proteins by regulating YAP, inhibit the maladaptive repair of renal tubular epithelial cells, and prevent the AKI-CKD transition.
Keywords: 14-3-3ζ; YAP; acute kidney injury; AKI-CKD transition; ischemia-reperfusion injury; renal fibrosis

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