A kinome-wide screen identifies a CDKL5-SOX9 regulatory axis in epithelial cell death and kidney injury

Kim, Ji Young; Bai, Yuntao; Jayne, Laura A.; Hector, Ralph D.; Persaud, Avinash K.; Ong, Su Sien; Rojesh, Shreshtha; Raj, Radhika; Feng, Mei Ji He Ho; Chung, Sangwoon; Cianciolo, Rachel E.; Christman, John W.; Campbell, Moray J.; Gardner, David S.; Baker, Sharyn D.; Sparreboom, Alex; Govindarajan, Rajgopal; Singh, Harpreet; Chen, Taosheng; Poi, Ming; Susztak, Katalin; Cobb, Stuart R.; Pabla, Navjot Singh

Abstract

© 2020, The Author(s). Renal tubular epithelial cells (RTECs) perform the essential function of maintaining the constancy of body fluid composition and volume. Toxic, inflammatory, or hypoxic-insults to RTECs can cause systemic fluid imbalance, electrolyte abnormalities and metabolic waste accumulation- manifesting as acute kidney injury (AKI), a common disorder associated with adverse long-term sequelae and high mortality. Here we report the results of a kinome-wide RNAi screen for cellular pathways involved in AKI-associated RTEC-dysfunction and cell death. Our screen and validation studies reveal an essential role of Cdkl5-kinase in RTEC cell death. In mouse models, genetic or pharmacological Cdkl5 inhibition mitigates nephrotoxic and ischemia-associated AKI. We propose that Cdkl5 is a stress-responsive kinase that promotes renal injury in part through phosphorylation-dependent suppression of pro-survival transcription regulator Sox9. These findings reveal a surprising non-neuronal function of Cdkl5, identify a pathogenic Cdkl5-Sox9 axis in epithelial cell-death, and support CDKL5 antagonism as a therapeutic approach for AKI.

Citation

Kim, J. Y., Bai, Y., Jayne, L. A., Hector, R. D., Persaud, A. K., Ong, S. S., …Pabla, N. S. (2020). A kinome-wide screen identifies a CDKL5-SOX9 regulatory axis in epithelial cell death and kidney injury. Nature Communications, 11(1), Article 1924. https://doi.org/10.1038/s41467-020-15638-6

• Journal Article Type: Article
• Acceptance Date: Mar 21, 2020
• Online Publication Date: Apr 21, 2020
• Publication Date: Dec 1, 2020
• Deposit Date: Apr 25, 2020
• Publicly Available Date: Apr 27, 2020
• Journal: Nature Communications
• Electronic ISSN: 2041-1723
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 11
• Issue: 1
• Article Number: 1924
• DOI: https://doi.org/10.1038/s41467-020-15638-6
• Keywords: General Biochemistry, Genetics and Molecular Biology; General Physics and Astronomy; General Chemistry
• Public URL: https://nottingham-repository.worktribe.com/output/4336526
• Publisher URL: https://www.nature.com/articles/s41467-020-15638-6
• Additional Information: Received: 10 November 2018; Accepted: 21 March 2020; First Online: 21 April 2020; : The authors declare no competing interests.