Inhibition of Transglutaminase 2 Reduces Peritoneal Injury in a Chlorhexidine-Induced Peritoneal Fibrosis Model

Area of Science:

• Nephrology
• Cell Biology
• Pathology

Background:

• Long-term peritoneal dialysis (PD) can lead to peritoneal dysfunction, characterized by fibrosis and angiogenesis, often resulting in PD withdrawal.
• The precise mechanisms underlying peritoneal dysfunction and potential therapeutic targets remain largely unidentified.
• Transglutaminase 2 (TG2) is explored as a novel therapeutic target for peritoneal injury.

Purpose of the Study:

• To investigate the role of TG2 in peritoneal inflammation and fibrosis, specifically in a chlorhexidine gluconate (CG)-induced model.
• To evaluate the therapeutic potential of TG2 inhibition for ameliorating peritoneal injuries associated with PD.

Main Methods:

• A chlorhexidine gluconate (CG)-induced rat model of peritoneal inflammation and fibrosis was used.
• Studies involved TG2 inhibition using TG2-knockout mice and a transforming growth factor-beta type I receptor (TGFβR-I) inhibitor.
• Double immunostaining was employed to detect TG2 expression, myofibroblasts, endothelial cells, macrophages, and endothelial-mesenchymal transition (EndMT).

Main Results:

• In the CG model, TG2 activity and expression increased with peritoneal fibrosis, thickness, and angiogenesis.
• TGFβR-I inhibitor and TG2 knockout suppressed TG2 activity, peritoneal fibrosis, and angiogenesis.
• TG2 was implicated in endothelial-mesenchymal transition (EndMT) and its inhibition reduced this process.

Conclusions:

• TG2 is involved in the pathogenesis of peritoneal fibrosis, inflammation, and angiogenesis in PD.
• Inhibition of TG2 reduces peritoneal injury by suppressing TGF-β and vascular endothelial growth factor-A.
• TG2 represents a potential therapeutic target for managing peritoneal dysfunction in patients undergoing PD.