SALL1 Is Essential for Histone H3K27 Methyltransferase EZH2 to Regulate Apoptotic Responses in Kidney Ischemia-Reperfusion Injury

Background: The role of histone methylation modifications in renal disease, particularly in ischemia/reperfusion-induced acute kidney injury (AKI), remains unclear. This study aims to investigate the potential involvement of the histone methyltransferase zeste homolog 2 (EZH2) in ischemia/reperfusion-induced AKI and its impact on apoptosis. Methods: We first examined the expression of EZH2 in the kidney of ischemia/reperfusion-induced AKI mice and hypoxia-stimulated tubular epithelial cells. We next constructed the EZH2 knockout mice to further confirm the effects of EZH2 on apoptosis response in AKI. Subsequently, we constructed the EZH2 knocked-down cells again and performed Chromatin Immunoprecipitation sequencing to screen out the target genes regulated by EZH2 and the enrichment pathway. Then we confirmed the EZH2 target gene and its regulatory pathway in vivo and in vitro experiments. Results: The study found that EZH2 was upregulated in ischemia/reperfusion-induced AKI and that silencing EZH2 could reduce renal tubular injury by decreasing apoptosis response of tubular epithelial cells. Chromatin immunoprecipitation sequencing and polymerase chain reaction identified SALL1 as a target of EZH2. EZH2 was found to be enriched on the promoter of SALL1. Silencing EZH2 resulted in a significant increase in the transcriptional level of SALL1 and activation of the Wnt/β-catenin signaling pathway. The study further reversed the effects of EZH2 silencing by silencing SALL1 or administering the Wnt/β-catenin inhibitor icg001. It was also found that SALL1 positively regulated the expression of Wnt/β-catenin pathway-related genes. Finally, the study showed that the EZH2 inhibitor GSK-126 significantly alleviated ischemia/reperfusion-induced AKI. Conclusion: Our results indicate that silencing EZH2 can protect renal function by relieving transcriptional inhibition of SALL1, activating the Wnt/β-catenin pathway, and attenuating tubular epithelial apoptosis response. These results highlight the potential therapeutic value of targeting EZH2 in ischemia/reperfusion-induced AKI.