Abstract: FR-PO459
Decorin Deficiency Accelerates Peritoneal Fibrosis in a Murine Model of Peritoneal Dialysis
Session Information
- Peritoneal Dialysis: Current Topics
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Dialysis
- 702 Dialysis: Home Dialysis and Peritoneal Dialysis
Authors
- Mok, Wing Long Cody, Department of Medicine, School of Clinical Medicine, the University of Hong Kong, Hong Kong SAR, Hong Kong
- Wu, Rafter Y. F., Department of Medicine, School of Clinical Medicine, the University of Hong Kong, Hong Kong SAR, Hong Kong
- Oh, In Young, Department of Medicine, School of Clinical Medicine, the University of Hong Kong, Hong Kong SAR, Hong Kong
- Iozzo, Renato V., Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States
- Chan, Tak Mao Daniel, Department of Medicine, School of Clinical Medicine, the University of Hong Kong, Hong Kong SAR, Hong Kong
- Yung, Susan, Department of Medicine, School of Clinical Medicine, the University of Hong Kong, Hong Kong SAR, Hong Kong
Background
Preservation of structural and functional integrity of the peritoneal membrane is a major challenge limiting the feasibility of long-term peritoneal dialysis (PD). Decorin is a soluble dermatan sulphate proteoglycan, synthesized by peritoneal mesothelial cells, with anti-fibrotic properties. We investigated the role of decorin in a murine PD model.
Methods
Wild-type (WT) and decorin-knockout (DKO) mice were randomized to receive saline (Control) or glucose-based PD fluid containing 40 mM methylglyoxal (PDF Group) by intra-peritoneal injection, twice daily for up to 12 weeks, after which time the parietal peritoneum was excised to investigate the expression of α-smooth muscle actin (α-SMA), collagen and fibronectin (FN). Human peritoneal mesothelial cells (HPMC) were isolated from omentum and incubated with spent dialysate from stable PD patients, in the presence or absence of decorin (1 μg/ml) for 24 h, and mediators of fibrosis assessed.
Results
After 12 weeks of treatment, PDF Group WT mice showed submesothelial thickening accompanied by decreased decorin expression and increased α-SMA, FN and collagen expression, with infiltration by F4/80+CD206+ macrophages and CD86+CD4+ T cells. The submesothelium was inhabitated with elongated fibroblast-like cells which were positive for α-SMA and collagen I suggestive of myofibroblasts. These abnormalities were exacerbated in DKO mice (P<0.05 compared with WT), and was observed earlier, after 8 weeks of treatment. In cultured HPMC, PDF induced the expression of FN and its extra domain A/B isoforms (EDA-FN and EDB-FN) through increased ERK, p38 MAPK and PI3K phosphorylation, while addition of decorin decreased FN, EDA-FN and EDB-FN expression by 56.5%, 46.7% and 50.0% respectively.
Conclusion
Our data suggest that decorin ameliorates PDF-induced peritoneal fibrosis through its effects on FN and inflammatory cell infiltration.
Funding
- Government Support – Non-U.S.