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A Novel Inhibitor of Methyltransferase SMYD2, AZ505 Protects Against Peritoneal Fibrosis in Mice
Taijing Xu1, Binbin Cui2, Feng Liu3
1Department of Nephrology, Affiliated Huishan Hospital of Xinglin College, Nantong University, Wuxi, China.
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.
Insights
AZ505, a SMYD2 inhibitor, reduces peritoneal fibrosis by blocking inflammation and angiogenesis. This study shows AZ505 effectively treats peritoneal fibrosis in a mouse model.
Area of Science:
- Biochemistry
- Cell Biology
- Pathology
Background:
- Peritoneal fibrosis is a complication of peritoneal dialysis.
- The role of SMYD2 in peritoneal fibrosis is unknown.
- AZ505 is a selective SMYD2 inhibitor with known antifibrotic effects in renal fibrosis.
Purpose of the Study:
- To investigate the effects of AZ505 on chlorhexidine gluconate (CG)-induced peritoneal fibrosis in a murine model.
- To explore the underlying mechanisms of AZ505's action in peritoneal fibrosis.
Main Methods:
- Murine model of peritoneal fibrosis induced by CG.
- Administration of AZ505.
- Assessment of SMYD2, H3K36me3, collagen I, fibronectin, CD31, CD68, α-SMA, Vimentin, E-cadherin, Snail, Twist, p-AKT, and PTEN expression.
- Evaluation of epithelial-to-mesenchymal transition (EMT).
Main Results:
- CG injection increased SMYD2 and H3K36me3 expression in peritoneal tissue.
- AZ505 inhibited SMYD2 and H3K36me3 expression.
- AZ505 attenuated CG-induced peritoneal fibrosis, collagen I, and fibronectin expression.
- AZ505 reduced angiogenesis (CD31) and macrophage infiltration (CD68).
- AZ505 inhibited CG-induced EMT by decreasing α-SMA, Vimentin, Snail, and Twist, and increasing E-cadherin.
- AZ505 inhibited AKT phosphorylation and increased PTEN expression.
Conclusions:
- AZ505 demonstrates protective effects against peritoneal fibrosis.
- AZ505 acts by inhibiting SMYD2-mediated methylation.
- AZ505 mitigates peritoneal fibrosis by suppressing EMT, inflammation, and angiogenesis.
