Targeting CDC42 for acute kidney injury therapy via orchestrating KLF2/HIF-1α/PINK1-mediated mitophagy

Acute kidney injury (AKI) is an unsolved global public health problem, requiring new effective therapies. Cytokinesis cycle 42 (CDC42) is a potent therapeutic target for multiple diseases, whereas its function in AKI remains unknown. Here we report that inhibition of CDC42 protects against AKI via orchestrating kruppel-like factor 2 (KLF2)/HIF-1α/PINK1-mediated mitophagy. We showed Cdc42 was not only abundantly expressed in murine renal tubular epithelial cells (RTECs) but also up-regulated in human and murine RTECs post cisplatin exposure, respectively. Then, administration of a CDC42 inhibitor in vivo and in vitro, conditional knockdown of Cdc42 in murine RTECs, and knockout of CDC42 in human RTECs abated cisplatin-caused mitochondrial dysfunction and kidney injury. Furthermore, by integratively using transcriptome sequencing, bioinformatics analysis, dual luciferase reporter assay, and chromatin immunoprecipitation, we found CDC42 inhibition alleviated mitochondrial dysfunction via KLF2/HIF-1α/PINK1-mediated mitophagy, during which CDC42 inhibition enhanced the promoter activity of KLF2, while KLF2 transcriptionally up-regulated HIF-1α, and HIF-1α subsequently transcriptionally up-regulated PINK1, the crucial regulator of mitophagy. Moreover, the function of KLF2 and HIF-1α in CDC42-mediated RTECs damage and mitochondrial dysfunction was verified. In conclusion, we uncovered the role and underlying mechanism of CDC42 in AKI, providing AKI patients with new therapeutic strategies.