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

Area of Science:

• Nephrology
• Molecular Biology
• Cell Biology

Background:

• Prolonged peritoneal dialysis (PD) often causes peritoneal fibrosis (PF).
• The molecular mechanisms underlying PF development require further elucidation.
• Identifying key signaling pathways involved in PF is crucial for therapeutic development.

Purpose of the Study:

• To investigate the role of the Rho-associated coiled-coil containing protein kinase (ROCK) signaling pathway, and its downstream targets MEF2A and EZH2, in the pathogenesis of peritoneal fibrosis.
• To explore the potential of targeting the ROCK/MEF2A/EZH2 axis for the treatment of PD-induced PF.

Main Methods:

• Established a rat model of PD and utilized human peritoneal mesothelial cells (HPMCs) in vitro.
• Administered the ROCK inhibitor fasudil and employed adeno-associated virus-mediated MEF2A knockdown in vivo.
• Conducted MEF2A knockdown, EZH2 overexpression, and fasudil treatment experiments on high glucose-stimulated HPMCs in vitro.
• Utilized dual-luciferase reporter and ChIP-qPCR assays to confirm gene promoter interactions.

Main Results:

• High glucose exposure upregulated MEF2A and EZH2 in HPMCs, promoting epithelial-mesenchymal transition (EMT).
• MEF2A knockdown suppressed high glucose-induced EZH2 upregulation and EMT; EZH2 overexpression reversed these effects.
• MEF2A was confirmed to bind and activate the EZH2 promoter.
• ROCK inhibition with fasudil reversed high glucose-induced MEF2A changes and suppressed PF development in vivo.
• MEF2A knockdown alleviated PF in rats undergoing PD.

Conclusions:

• A novel ROCK/MEF2A/EZH2 signaling axis is implicated in the pathogenesis of peritoneal fibrosis.
• MEF2A plays a critical role in mediating the effects of high glucose and ROCK signaling on PF.
• MEF2A represents a potential therapeutic target for preventing or treating peritoneal fibrosis associated with peritoneal dialysis.