A renal YY1-KIM1-DR5 axis regulates the progression of acute kidney injury

Chen Yang, Huidie Xu, Dong Yang, Yunhao Xie, Mingrui Xiong, Yu Fan, XiKai Liu, Yu Zhang, Yushuo Xiao, Yuchen Chen, Yihao Zhou, Liangliang Song, Chen Wang, Anlin Peng, Robert B. Petersen, Hong Chen (), Kun Huang () and Ling Zheng ()
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Chen Yang: Huazhong University of Science and Technology
Huidie Xu: Huazhong University of Science and Technology
Dong Yang: Huazhong University of Science and Technology
Yunhao Xie: Wuhan University
Mingrui Xiong: Huazhong University of Science and Technology
Yu Fan: Wuhan University
XiKai Liu: Wuhan University
Yu Zhang: Huazhong University of Science and Technology
Yushuo Xiao: Huazhong University of Science and Technology
Yuchen Chen: Huazhong University of Science and Technology
Yihao Zhou: Wuhan University
Liangliang Song: Huazhong University of Science and Technology
Chen Wang: Huazhong University of Science and Technology
Anlin Peng: Tongren Hospital of Wuhan University
Robert B. Petersen: Central Michigan University College of Medicine
Hong Chen: Huazhong University of Science and Technology
Kun Huang: Huazhong University of Science and Technology
Ling Zheng: Wuhan University

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Acute kidney injury (AKI) exhibits high morbidity and mortality. Kidney injury molecule-1 (KIM1) is dramatically upregulated in renal tubules upon injury, and acts as a biomarker for various renal diseases. However, the exact role and underlying mechanism of KIM1 in the progression of AKI remain elusive. Herein, we report that renal tubular specific knockout of Kim1 attenuates cisplatin- or ischemia/reperfusion-induced AKI in male mice. Mechanistically, transcription factor Yin Yang 1 (YY1), which is downregulated upon AKI, binds to the promoter of KIM1 and represses its expression. Injury-induced KIM1 binds to the ECD domain of death receptor 5 (DR5), which activates DR5 and the following caspase cascade by promoting its multimerization, thus induces renal cell apoptosis and exacerbates AKI. Blocking the KIM1-DR5 interaction with rationally designed peptides exhibit reno-protective effects against AKI. Here, we reveal a YY1-KIM1-DR5 axis in the progression of AKI, which warrants future exploration as therapeutic targets.

Date: 2023
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DOI: 10.1038/s41467-023-40036-z

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