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Inhibition of polycomb repressive complex 2 by targeting EED protects against cisplatin-induced acute kidney injury.

ABSTRACT: 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.

SUBMITTER: Yu C

PROVIDER: S-EPMC9279598 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The histone methyltransferase SET and MYND domain protein 2 (SMYD2) has been implicated in tumorigenesis through methylating histone H3 at lysine36 (H3K36) and some non-histone substrates. Currently, the role of SMYD2 in acute kidney injury (AKI) remains unknown. Here, we investigated the effects of AZ505, a highly selective inhibitor of SMYD2, on the development of AKI and the mechanisms involved in a murine model of cisplatin-induced AKI. SMYD2 and trimethylated histone H3K36 (H3K36Me3) were highly expressed in the kidney following cisplatin treatment; administration of AZ505 remarkedly inhibited their expression, along with improving kidney function and ameliorating kidney damage. AZ505 also attenuated kidney tubular cell injury and apoptosis as evidenced by diminished the expression of neutrophil gelatinase associated lipocalin (NGAL) and kidney injury molecule (Kim-1), reduced the number of TUNEL positive cells, decreased the expression of cleaved caspase-3 and the BAX/BCL-2 ratio in injured kidneys. Moreover, AZ505 inhibited cisplatin-induced phosphorylation of p53, a key driver of kidney cell apoptosis and reduced expression of p21, a cell cycle inhibitor. Meanwhile, AZ505 promoted expression of proliferating cell nuclear antigen and cyclin D1, two markers of cell proliferation. Furthermore, AZ505 was effective in suppressing the phosphorylation of STAT3 and NF-κB, two transcriptional factors associated with kidney inflammation, attenuating the expression of monocyte chemoattractant protein-1 and intercellular cell adhesion molecule-1 and reducing infiltration of F4/80+ macrophages to the injured kidney. Finally, in cultured HK-2 cells, silencing of SMYD2 by specific siRNA inhibited cisplatin-induced apoptosis of kidney tubular epithelial cells. Collectively, these results suggests that SMYD2 is a key determinant of cisplatin nephrotoxicity and targeting SMYD2 protects against cisplatin-induced AKI by inhibiting apoptosis and inflammation and promoting cell proliferation.