Polycomb repressive complex 2 (PRC2) is a multicomponent complex with
methyltransferase activity that catalyzes trimethylation of
histone H3 at
lysine 27 (H3K27me3). Interaction of the epigenetic reader
protein EED with EZH2, a catalytic unit of PRC, allosterically stimulates PRC2 activity. In this study, we investigated the role and underlying mechanism of the PRC2 in
acute kidney injury (AKI) by using
EED226, a highly selective PRC2 inhibitor, to target EED. Administration of
EED226 improved renal function, attenuated renal pathological changes, and reduced renal tubular cell apoptosis in a murine model of
cisplatin-induced AKI. In cultured renal epithelial cells, treatment with either
EED226 or EED
siRNA also ameliorated
cisplatin-induced apoptosis. Mechanistically,
EED226 treatment inhibited
cisplatin-induced phosphorylation of p53 and FOXO3a, two transcriptional factors contributing to apoptosis, and preserved expression of
Sirtuin 3 and PGC1α, two
proteins associated with mitochondrial protection in vivo and in vitro.
EED226 was also effective in enhancing renal tubular cell proliferation, suppressing expression of multiple inflammatory
cytokines, and reducing infiltration of macrophages to the injured kidney. These data suggest that inhibition of the PRC2 activity by targeting EED can protect against
cisplatin-induced AKI by promoting the survival and proliferation of renal tubular cells and inhibiting inflammatory response.