MEF2A nuclear translocation mediated by ROCK phosphorylation promotes EZH2 expression and peritoneal fibrosis.

Prolonged peritoneal dialysis (PD) frequently leads to peritoneal fibrosis (PF). This study aimed to define the role of the Rho-associated coiled-coil containing protein kinase (ROCK) signaling pathway and its downstream effectors, MEF2A and EZH2, in PF. In vivo, a rat PD model was treated with the ROCK inhibitor fasudil or adeno-associated virus-mediated MEF2A knockdown. In vitro, high glucose-stimulated human peritoneal mesothelial cells (HPMCs) were subjected to MEF2A knockdown, EZH2 overexpression, or fasudil treatment. Exposure of HPMCs to high glucose markedly upregulated total and phosphorylated MEF2A (p-MEF2A) and promoted its nuclear translocation. MEF2A knockdown suppressed high glucose-induced upregulation of EZH2 and epithelial-mesenchymal transition (EMT), whereas EZH2 overexpression reversed this protective effect. Dual-luciferase reporter and ChIP-qPCR assays confirmed that MEF2A binds to the EZH2 promoter and activates its transcription. Inhibition of the ROCK pathway with fasudil reversed the high glucose-induced upregulation of MEF2A and suppressed its phosphorylation and nuclear translocation. In vivo, MEF2A knockdown alleviated PF in rats undergoing to long-term PD. Consistently, oral fasudil treatment inhibited the dialysis-induced upregulation of MEF2A and EMT markers. These results reveal a novel ROCK/MEF2A/EZH2 axis in PF pathogenesis, highlighting MEF2A as a potential therapeutic target.