Inhibition of HDAC8 mitigates AKI by reducing DNA damage and promoting homologous recombination repair

Abstract Nephrotoxicity is a major side effect of platinum‐based antineoplastic drugs, and there is currently no available therapeutic intervention. Our study suggests that targeting histone deacetylase 8 could be a potential treatment for cisplatin‐induced acute kidney injury (AKI). In a murine model of AKI induced by cisplatin, the administration of PCI‐34051, a selective inhibitor of HDAC8, resulted in significant improvement in renal function and reduction in renal tubular damage and apoptosis. Pharmacological inhibition of HDAC8 also decreased caspase‐3 and PARP1 cleavage, attenuated Bax expression and preserved Bcl‐2 levels in the injured kidney. In cultured murine renal epithelial cells (mRTECs) exposed to cisplatin, treatment with PCI‐34051 or transfection with HDAC8 siRNA reduced apoptotic cell numbers and diminished expression of cleaved caspase‐3 and PARP1; conversely, overexpression of HDAC8 intensified these changes. Additionally, PCI‐34051 reduced p53 expression levels along with those for p21, p‐CDK2 and γ‐H2AX while preserving MRE11 expression in the injured kidney. Similarly, pharmacological and genetic inhibition of HDAC8 reduced γ‐H2AX and enhanced MRE11 expression; conversely, HDAC8 overexpression exacerbated these changes in mRTECs exposed to cisplatin. These results support that HDAC8 inhibition attenuates cisplatin‐induced AKI through a mechanism associated with reducing DNA damage and promoting its repair.