Pressure induces peritoneal fibrosis and inflammation through CD44 signaling.

ABSTRACT

Peritoneal dialysis (PD) is a widely used sustainable kidney replacement therapy. Prolonged use of PD fluids is associated with mesothelial-mesenchymal transition, peritoneal fibrosis, and eventual ultrafiltration (UF) failure. However, the impact of pressure on the peritoneum remains unclear. In the present study, we hypothesized increased pressure is a potential contributing factor to peritoneal fibrosis and investigated the possible mechanisms. In vitro experiments found that pressurization led to a mesenchymal phenotype, the expression of fibrotic markers and inflammatory factors in human mesothelial MeT-5A cells. Pressure also increased cell proliferation and augmented cell migration potential in MeT-5A cells. The mouse PD model and human peritoneum equilibrium test (PET) data both showed a positive association between higher pressure and increased small solute transport, along with decreased net UF. Mechanistically, we found that significant upregulation of CD44 in mesothelial cells upon pressurization. Notably, the treatment of CD44 neutralizing antibodies prevented pressure-induced phenotypic changes in mesothelial cells, while a CD44 inhibitor oligo-fucoidan ameliorated pressure-induced peritoneal thickening, fibrosis, and inflammation in PD mice. To conclude, intraperitoneal pressure results in peritoneal fibrosis in PD via CD44-mediated mesothelial changes and inflammation. CD44 blockage can be utilized as a novel preventive approach for PD-related peritoneal fibrosis and UF failure.