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

Nat Commun. 2020 Apr 21;11(1):1924. doi: 10.1038/s41467-020-15638-6.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / metabolism*
  • Animals
  • Cell Death
  • Epithelial Cells / cytology*
  • Epithelial Cells / metabolism
  • Female
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Keratinocytes / metabolism
  • Kidney / metabolism
  • Kidney Tubules / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons / metabolism
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • SOX9 Transcription Factor / metabolism*

Substances

  • RNA, Small Interfering
  • SOX9 Transcription Factor
  • SOX9 protein, human
  • Sox9 protein, mouse
  • Green Fluorescent Proteins
  • Protein-Serine-Threonine Kinases
  • CDKL5 protein, human
  • CDKL5 protein, mouse