Extracellular vesicles of patients on peritoneal dialysis inhibit the TGF-β and PDGF-B mediated fibrotic processes

Abstract

Abstract Background: Peritoneal fibrosis develops in 50%-80%, and life-threatening encapsulating peritoneal sclerosis (EPS) in 0.5-4.4% of the patients on peritoneal dialysis (PD). Here we investigated the role of extracellular vesicles (EVs) on the transforming growth factor (TGF)-β and platelet derived growth factor (PDGF)-B driven processes of peritoneal fibrosis. EVs were isolated from the peritoneal dialysis effluent (PDE) of children receiving continuous ambulatory peritoneal dialysis (PD). The impact of PDE-EVs on the epithelial-mesenchymal transition (EMT) and collagen production of the peritoneal mesothelial cells and fibroblasts were investigated in vitro, and in vivo in the chlorhexidine digluconate (CG) induced mice model of peritoneal fibrosis. Results: PDE-EVs showed spherical morphology in the 100 nm size range, their spectral features, CD63, and annexin positivity was characteristic to EVs. PDE-EVs penetrated into the peritoneal mesothelial cells and fibroblasts and reduced their PDE or PDGF-B induced proliferation. Furthermore, PDE-EVs inhibited the PDE or TGF-β induced EMT and collagen production of the investigated cell types. PDE-EVs contributed to the mesothelial layer integrity and decreased submesothelial thickening of CG-treated mice. Conclusions: We demonstrated that PDE-EVs significantly inhibit the PDGF-B or TGF-β induced fibrotic processes in vitroand in vivo, suggesting that EVs may contribute to new therapeutic strategies to treat peritoneal fibrosis and other fibroproliferative diseases.