GSK343, an inhibitor of EZH2, mitigates fibrosis and inflammation mediated by HIF-1α in human peritoneal mesothelial cells treated with high glucose

Inflammation and fibrosis in peritoneal mesothelial cells caused by long-term peritoneal dialysis (PD) are the main reasons why patients withdraw from peritoneal dialysis treatment. However, the related mechanism is still unclear. In the current study, we revealed that the expression of EZH2 was positively related to EMT and fibrosis in an in vitro model using human peritoneal mesothelial cells (HPMCs) stimulated with high glucose. Moreover, EZH2 also exhibited a positive correlation with HIF-1α expression. Using an sh-RNA lentivirus specific to EZH2, the EZH2 Inhibitor GSK343 and rescue experiments of HIF-1α, we showed that EZH2 was an inducer of inflammation and fibrosis mediated by HIF-1α. Mechanistically, we revealed that on the one hand, EZH2 could increase the trimethylation of H3K4 at the HIF-1α gene promoter and directly activate HIF-1α transcription, as demonstrated by co-IP and ChIP-RT-PCR experiments. On the other hand, we verified that EZH2 could increase the trimethylation of H3K27 at the miR-142 gene promoter, which repressed the expression of miR-142. Combining bioanalysis and dual-luciferase assays, we found that miR-142 could regulate HIF-1α expression by directly binding to its mRNA 3'-UTR. Inhibition of miR-142 could rescue the protective effect of GSK343 on inflammation and fibrosis. In conclusion, our current study revealed that EZH2 plays a vital role in peritoneal fibrosis mediated by HIF-1α and related mechanisms. To our knowledge, this is the first study to demonstrate the effect of the EZH2-HIF-1α interaction and miR-142 on peritoneal fibrosis and inflammation and to suggest EZH2 and miR-142 as potential targets for the treatment of peritoneal fibrosis in patients with PD.