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Hyperglycemia-mediated reactive oxygen species (ROS)accumulation plays an important role in hyperglycemia-induced endothelial injury.Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway inhibition participates in hyperglycemia-induced ROS accumulation.Our previous study indicated that SET8 overexpression inhibits high glucose-mediated ROS accumulation in human umbilical vein endothelial cells (HUVECs).In the present study,we hypothesize that SET8 may play a major role in high glucose-induced ROS accumulation via modulation of Keap1/Nrf2/ARE pathway.Our data indicated that high glucose mediated cell viability reduction,ROS accumulation,and Nrf2/ARE signal pathway inhibition via upregulation of Keap1 expression in HUVECs.Moreover,high glucose inhibited the expressions of SET8 and H4K20me1 (a downstream target of SET8).SET8 overexpression improved high glucose-mediated Keap1/Nrf2/ARE pathway inhibition and endothelial oxidation.Consistently,the effects of sh-SET8 were similar to that of high glucose treatment and were reversed by si-Keap1.A mechanistic study found that H4K20me1 was enriched at the Keap1 promoter region.SET8 overexpression attenuated Keap1 promoter activity and its expression,while mutant SET8 R259G did not affect Keap1 promoter activity and expression.The results of this study demonstrated that SET8 negatively regulates Keap1 expression,thus participating in high glucose-mediated Nrf2/ARE signal pathway inhibition and oxidative injury in HUVECs.