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., Rojesh, S., Raj, R., Feng, M. J. H. H., Chung, S., Cianciolo, R. E., Christman, J. W., Campbell, M. J., Gardner, D. S., Baker, S. D., Sparreboom, A., Govindarajan, R., Singh, H., Chen, T., Poi, M., …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.