TP53RK Drives the Progression of Chronic Kidney Disease by Phosphorylating Birc5

Author:

Wu Mengqiu1ORCID,Jin Qianqian1,Xu Xinyue2,Fan Jiaojiao2,Chen Weiyi3,Miao Mengqiu1,Gu Ran1,Zhang Shengnan1,Guo Yan1,Huang Songming1,Zhang Yue1,Zhang Aihua1,Jia Zhanjun1ORCID

Affiliation:

1. Department of Nephrology Nanjing Key Laboratory of Pediatrics Jiangsu Key Laboratory of Pediatrics Children's Hospital of Nanjing Medical University Nanjing Medical University Nanjing 210008 P. R. China

2. School of Medicine Southeast University Nanjing 210009 P. R. China

3. Department of Emergency Medicine Children's Hospital of Nanjing Medical University Nanjing 210008 P. R. China

Abstract

AbstractRenal fibrosis is a common characteristic of various chronic kidney diseases (CKDs) driving the loss of renal function. During this pathological process, persistent injury to renal tubular epithelial cells and activation of fibroblasts chiefly determine the extent of renal fibrosis. In this study, the role of tumor protein 53 regulating kinase (TP53RK) in the pathogenesis of renal fibrosis and its underlying mechanisms is investigated. TP53RK is upregulated in fibrotic human and animal kidneys with a positive correlation to kidney dysfunction and fibrotic markers. Interestingly, specific deletion of TP53RK either in renal tubule or in fibroblasts in mice can mitigate renal fibrosis in CKD models. Mechanistic investigations reveal that TP53RK phosphorylates baculoviral IAP repeat containing 5 (Birc5) and facilitates its nuclear translocation; enhanced Birc5 displays a profibrotic effect possibly via activating PI3K/Akt and MAPK pathways. Moreover, pharmacologically inhibiting TP53RK and Birc5 using fusidic acid (an FDA‐approved antibiotic) and YM‐155(currently in clinical phase 2 trials) respectively both ameliorate kidney fibrosis. These findings demonstrate that activated TP53RK/Birc5 signaling in renal tubular cells and fibroblasts alters cellular phenotypes and drives CKD progression. A genetic or pharmacological blockade of this axis serves as a potential strategy for treating CKDs.

Funder

National Key Research and Development Program of China

Publisher

Wiley

Subject

General Physics and Astronomy,General Engineering,Biochemistry, Genetics and Molecular Biology (miscellaneous),General Materials Science,General Chemical Engineering,Medicine (miscellaneous)

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