Hyperactivation of p53 contributes to mitotic catastrophe in podocytes through regulation of the Wee1/CDK1/cyclin B1 axis

Abstract

Podocyte loss in glomeruli is a fundamental event in the pathogenesis of chronic kidney diseases. Currently, mitotic catastrophe (MC) has emerged as the main cause of podocyte loss. However, the regulation of MC in podocytes has yet to be elucidated. The current work aimed to study the role and mechanism of p53 in regulating the MC of podocytes using adriamycin (ADR)-induced nephropathy. In vitro podocyte stimulation with ADR triggered the occurrence of MC, which was accompanied by hyperactivation of p53 and cyclin-dependent kinase (CDK1)/cyclin B1. The inhibition of p53 reversed ADR-evoked MC in podocytes and protected against podocyte injury and loss. Further investigation showed that p53 mediated the activation of CDK1/cyclin B1 by regulating the expression of Wee1. Restraining Wee1 abolished the regulatory effect of p53 inhibition on CDK1/cyclin B1 and rebooted MC in ADR-stimulated podocytes via p53 inhibition. In a mouse model of ADR nephropathy, the inhibition of p53 ameliorated proteinuria and podocyte injury. Moreover, the inhibition of p53 blocked the progression of MC in podocytes in ADR nephropathy mice through the regulation of the Wee1/CDK1/cyclin B1 axis. Our findings confirm that p53 contributes to MC in podocytes through regulation of the Wee1/CDK1/Cyclin B1 axis, which may represent a novel mechanism underlying podocyte injury and loss during the progression of chronic kidney disorder.

Keywords:

• CDK1
• cyclin B1
• p53
• podocyte
• mitotic catastrophe
• Wee1

Authors’ contributions

Jie Feng designed the study, performed the experiments and wrote the manuscript. Liyi Xie, Wanhong Lu, and Hongjuan Dong performed the experiments. Xiaoyang Yu and Yuefeng Ma performed the data analysis and provided technical support. Ranran Kong contributed to the conceptualization and reviewed the manuscript. All the authors reviewed and approved the final version of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Ethical approval

All the experimental protocols for the animal studies were approved by The Biomedical Ethics Committee of Health Science Center of Xi’an Jiaotong University (No. 2021-432). Animal experiments complied with the ARRIVE guidelines and were carried out in accordance with the National Research Council’s Guide for the Care and Use of Laboratory Animals.

Data availability statement

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Additional information

Funding

Jie Feng is supported by the National Natural Science Foundation of China (NSFC) (82100718) and the Key R&D Program of Shaanxi Province (2022SF-116). Ranran Kong was supported by the National Natural Science Foundation of China (NSFC) (82373002) and the Clinical Research Special Fund of Wu Jieping Medical Foundation (320.6750.2023-05-15). Yuefeng Ma is supported by the Key R&D Program of Shaanxi Province (2022SF-235).