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

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ID: 104815
2020
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Abstract
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.
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kim2020anature Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors 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;
Journal Nature communications
Year 2020
DOI
10.1038/s41467-020-15638-6
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