Tubular aryl hydrocarbon receptor upregulates EZH2 to promote cell senescence in cisplatin-induced acute kidney injury

Abstract

Acute kidney injury (AKI) is one of the serious clinical syndromes with high morbidity and mortality. Despite substantial progress in understanding of AKI mechanism, no drug therapy is available for treatment or prevention. In this study, we identified that a ligand-activated transcription factor aryl hydrocarbon receptor (AhR) was highly expressed in the kidneys of cisplatin-induced AKI mice or tubular epithelial TCMK-1 cells. Notably, the AhR inhibition by BAY2416964 and tubular conditional deletion both alleviated cisplatin-induced kidney injury and cellular senescence, which was indicated by senescence-associated β-galactosidase (SA-β-gal) activity, biomarker p53, p21, p16 protein expression, and secretory phenotype IL-1β, IL-6 and TNFα level. Mechanistically, the abnormal AhR expression was positively correlated with the elevated EZH2, a methyltransferase. In addition, AhR inhibition also could suppress the EZH2 expression in the cisplatin-injured kidneys. Furthermore, the ChIP assay displayed that EZH2 may indirectly interact with AhR promoter region by affecting H3K27me3. The direct recruitment between H3K27me3 and AhR promoter is higher in the kidneys of control than that of cisplatin mice, suggesting EZH2 could reversely regulate the AhR expression through weakening H3K27me3 transcriptional inhibition on AhR promoter. Collectively, the present study implicated that AhR and EZH2 have mutual regulation, which further accelerated tubular cellular senescence in cisplatin-induced AKI.