Involvement of the CDKL5-SOX9 signaling axis in rhabdomyolysis-associated acute kidney injury.

Involvement of the CDKL5-SOX9 signaling axis in rhabdomyolysis-associated acute kidney injury. Am J Physiol Renal Physiol. 2020 Oct 12;: Authors: Kim JY, Bai Y, Jayne LA, Cianciolo RE, Bajwa A, Pabla NS Abstract Acute kidney injury (AKI) is a common clinical syndrome associated with adverse short and long-term sequelae. Renal tubular epithelial cell (RTECs) dysfunction and cell death are among the key pathological features of AKI. Diverse systemic and localized stress conditions such as sepsis, rhabdomyolysis, cardiac surgery, and nephrotoxic drugs can trigger RTEC dysfunction. Through an unbiased RNAi screen, we recently identified cyclin-dependent kinase-like 5 (Cdkl5) also known as serine/threonine kinase 9 as a critical regulator of RTEC dysfunction associated with nephrotoxic and ischemia-associated AKI. In the current study, we have examined the role of Cdkl5 in rhabdomyolysis-associated AKI. Using activation-specific antibodies and kinase assays, we found that Cdkl5 is activated in RTECs, early during the development of rhabdomyolysis-associated AKI. Furthermore, we found that RTEC-specific Cdkl5 gene ablation mitigates rhabdomyolysis-associated renal impairment. In addition, a small molecule kinase inhibitor AST-487 alleviated rhabdomyolysis-associated AKI in a Cdkl5-dependent manner. Mechanistically, we demonstrate that Cdkl5 phosphorylates the transcriptional regulator Sox9 and suppresses its protective function under stres...
Source: American Journal of Physiology. Renal Physiology - Category: Physiology Authors: Tags: Am J Physiol Renal Physiol Source Type: research