Cannabinoid receptors as therapeutic targets for dialysis-induced peritoneal fibrosis

Background: Long-term exposure to bioincompatible peritoneal dialysis solutions is frequently complicated with peritoneal fibrosis and ultrafiltration failure. As cannabinoid receptor (CBR) ligands have been reported to be beneficial to ameliorate the process of liver fibrosis, we strove to investigate their therapeutic potential to prevent peritoneal fibrosis. Methods: We used the rat model of peritoneal fibrosis induced by intraperitoneal injection of methylglyoxal and in vitro mesothelial cell culture to test the effects of CBR ligands, including the type 1 CBR (CB₁R) antagonist and the type 2 CBR (CB₂R) agonist. Results: In the methylglyoxal model, both intraperitoneal CB₁R antagonist (AM281) and CB₂R agonist (AM1241) treatment significantly ameliorated peritoneal fibrosis. In addition, CB₁R antagonist was able to alleviate TGF-β₁-induced dedifferentiation of mesothelial cells and to maintain epithelial integrity in vitro. Conclusions: Intraperitoneal administration of CBR ligands (CB ₁R antagonist and CB₂R agonist) offers a potential therapeutic strategy to reduce dialysis-induced peritoneal fibrosis and to prolong the peritoneal survival in peritoneal dialysis patients.