Tubular EZH2 promotes acute kidney injury by Inhibiting SDHC-mediated mitochondrial function.

BACKGROUND

Acute kidney injury (AKI) is a clinical syndrome characterized by a rapid decline in renal function and is associated with high morbidity and mortality. Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, has been implicated in promoting AKI progression. However, the downstream mechanisms through which EZH2 acts in AKI remain poorly understood.

METHODS

Public transcriptomic, spatial transcriptomic, and single-cell transcriptomic datasets from human and mouse acute kidney injury (AKI) samples were analyzed to characterize EZH2 expression. A tubule-specific Ezh2 knockout mouse model was established. AKI was induced by cisplatin injection or ischemia-reperfusion injury (IRI), followed by assessment of renal function and injury markers. Integrated RNA-seq and EZH2 ChIP-seq analyses were performed to identify downstream targets. Cisplatin-treated human renal tubular epithelial cells served as an in vitro AKI model.

RESULTS

EZH2 was significantly upregulated in the kidneys of both human and mouse AKI, primarily localized to proximal tubules. Tubule-specific knockout of EZH2 markedly ameliorated the decline in renal function and tissue damage in both cisplatin and IRI models, as evidenced by reduced serum creatinine, decreased levels of the kidney injury marker KIM-1, and improved tissue architecture. Integrated RNA-seq and ChIP-seq analysis identified eight potential direct target genes of EZH2 involved in the oxidative phosphorylation pathway, with the mitochondrial Complex II subunit succinate dehydrogenase complex subunit C (SDHC) being a prominent candidate. CUT&Tag-qPCR demonstrated that EZH2 inhibition reduced the enrichment of both EZH2 and H3K27me3 at the SDHC promoter. Furthermore, EZH2 deletion restored SDHC expression, whereas treatment with an SDHC inhibition or deletion abolished the renoprotective and antioxidative effects of EZH2 deletion in two AKI animal models, indicating a dependence on mitochondrial Complex II function.

CONCLUSION

EZH2 promotes AKI progression by repressing SDHC expression. Restoring mitochondrial function through targeting EZH2 may represent a novel therapeutic strategy for AKI.