Role of CDKL1-SOX11 Signaling Axis in AKI

Background: The biology of CDKL (Cyclin-Dependent Kinase-Like) kinase family remains enigmatic. Contrary to their nomenclature, CDKLs do not rely on cyclins for activation and are not involved in cell cycle regulation. Instead, they share structural similarities with MAPKs (Mitogen-Activated Protein Kinases) and GSK3 (glycogen synthase kinase 3), though their specific functions and associated signaling pathways are still unknown. Previous studies have shown that the activation of CDKL5 kinase contributes to the development of acute kidney injury (AKI) by suppressing the protective SOX9-dependent transcriptional program in tubular epithelial cells. The role of other CDKL family members in kidney biology and disease remains unknown. Methods: Mouse models of renal ischemia reperfusion, and rhabdomyolysis were used to assess the effect or germline CDKL1 and tubular specific SOX11 conditional knockout mice in the severity of AKI. Results: In the current study, we measured the functional activity of all the five CDKL kinases and discovered that, in addition to CDKL5, CDKL1 is also activated in tubular epithelial cells during AKI. To explore the role of CDKL1, we generated a germline knockout mouse which exhibited no abnormalities under normal conditions. Notably, when these mice were challenged with bilateral ischemia reperfusion and rhabdomyolysis, they were found to be protected from AKI. Further mechanistic investigations revealed that CDKL1 phosphorylates and destabilizes SOX11, contributing to tubular dysfunction. In summary, these studies have unveiled a previously unknown CDKL1-SOX11 axis that drives tubular dysfunction during AKI. Conclusion: This study underscores the importance of CDKL1 kinase in kidney injury and supports the development of targeted small-molecule inhibitors as potential therapeutics. Funding: Other NIH Support - NCATS