Protective effect of COMP-angiopoietin-1 on peritoneal vascular permeability and peritoneal transport function in uremic peritoneal dialysis rats

摘要

The angiopoietin-1 (Ang-1)/Tie-2 signaling pathway plays a crucial role in the maintenance of vascular stabilization and permeability. In this study, we evaluated the protective effect of a designed Ang-1 variant (COMP-Ang-1) on peritoneal vascular permeability and peritoneal transport function in a uremic peritoneal dialysis (PD) model. Compared to the sham controls, uremic rats were characterized by decreased pericyte coverage and downregulated endothelial junction expression. The permeability of the peritoneal vasculature to FITC-BSA and FITC-dextran in uremic rats was also higher than that in the sham controls, as well as increased levels of proinflammatory adhesion molecules and cytokines, increased D/Pcr and decreased ultrafiltration. Such changes were more marked in uremia+PD rats after exposure to glucose-based peritoneal dialysis fluid (PDF) for 4 weeks. Peritoneal Ang-1 protein expression and Tie-2 phosphorylation were significantly lower in uremic rats than in control rats and were further significantly reduced in uremia+PD rats. After COMP-Ang-1 administration, phosphorylation of the Tie-2 receptor was significantly increased. Treatment with COMP-Ang-1 also significantly enhanced pericyte coverage, upregulated endothelial junction protein expression and inhibited leakage of FITC-BSA and FITC-dextran from the peritoneal vasculature induced during PD therapy; these changes were accompanied by reduced peritoneal tissue levels of proinflammatory adhesion molecules and cytokines, decreased D/Pcr and increased ultrafiltration. These findings suggest that COMP-Ang-1 may exert a protective effect against glucose-based PDF-induced peritoneal vascular permeability and inflammation, at least in part, by enhancing pericyte coverage and endothelial junction protein expression, which subsequently significantly improves peritoneal transport function.