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.
Highlights
Renal tubular epithelial cells (RTECs) perform the essential function of maintaining the constancy of body fluid composition and volume
Cisplatin-induced cell death was partially ameliorated by protein kinase c δ (Pkcδ) knockdown, which is an established[24] pro-apoptotic gene and significantly increased by polo-like kinase 1 (Plk1) knockdown
We investigated whether the increased Cdkl[5] activity is localized in the RTECs—the major cell type that is impacted during AKI7
Summary
Renal tubular epithelial cells (RTECs) perform the essential function of maintaining the constancy of body fluid composition and volume. We propose that Cdkl[5] is a stress-responsive kinase that promotes renal injury in part through phosphorylation-dependent suppression of pro-survival transcription regulator Sox[9] These findings reveal a surprising non-neuronal function of Cdkl[5], identify a pathogenic Cdkl5-Sox[9] axis in epithelial cell-death, and support CDKL5 antagonism as a therapeutic approach for AKI. RTEC dysfunction can lead to systemic electrolyte and fluid imbalances along with accumulation of metabolic and toxic waste triggering deleterious systemic effects and multi-organ failure Numerous clinical conditions such as sepsis, cardiac surgery, drug toxicities, cancer therapy, and rhabdomyolysis are associated with inflammatory, toxic, and hypoxic insults to RTECs2–6. We have used a kinome-wide screening approach to identify kinases that contribute to RTEC cell death in order to reveal therapeutic targets for AKI. We have uncovered a previously unrecognized function of Cdkl[5] as a crucial regulator of renal injury and identified the transcription factor Sox[9] as one of its crucial downstream target
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