A Novel Inhibitor of Methyltransferase SMYD2, AZ505 Protects Against Peritoneal Fibrosis in Mice

Abstract

AZ505, a highly selective inhibitor of SMYD2, exhibits an antifibrotic effect in renal fibrosis. Its effect on peritoneal fibrosis remains unexplored. In this study, we investigated its effects on the development of peritoneal fibrosis induced by chlorhexidine gluconate (CG) in a murine model. We found that SMYD2 and trimethylated histone substrate H3K36 (H3K36me3) were highly expressed in the peritoneal tissue following CG injection, and administration of AZ505 remarkably inhibited their expression, along with attenuating CG–induced peritoneal fibrosis and expression of collagen I and fibronectin. Moreover, AZ505 also significantly reduced expression of CD31 (marker of angiogenesis) and CD68-positive macrophage infiltration in the CG-injured peritoneum. AZ505 further inhibited CG-induced epithelial-to-mesenchymal transition (EMT) of peritoneal mesothelial cells, manifested by decreasing expression of α-smooth muscle antigen (α-SMA) and Vimentin and restoring E-cadherin expression, accompanied by suppressing expression of two transcription factors, Snail and Twist. Finally, AZ505 inhibited CG-induced phosphorylation of AKT and increased expression of phosphatase and tensin (PTEN), a key phosphatase. These data suggest that AZ505 may protect against peritoneal fibrosis by inhibiting EMT, inflammation and angiogenesis, due to its blockade of methylation modification catalysed by SMYD2.