Abstract: SA-PO436
Extra Domain A-Spliced Fibronectin Variant Contributes to Peritoneal Inflammation and Fibrosis in a Murine Model of Peritoneal Fibrosis
Session Information
- Home Dialysis - 2
October 26, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Dialysis
- 802 Dialysis: Home Dialysis and Peritoneal Dialysis
Authors
- Ullah, Sami, 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
- Wu, Rafter Y. F., Department of Medicine, School of Clinical Medicine, the University of Hong Kong, Hong Kong SAR, Hong Kong
- Chan, Tak Mao Daniel, Department of Medicine, School of Clinical Medicine, the University of Hong Kong, Hong Kong SAR, Hong Kong
Background
Peritoneal dialysis (PD) is an important mode of renal replacement therapy but preservation of the structural and functional integrity of the peritoneal membrane is a major challenge limiting the feasibility of long-term treatment. Onset of tissue fibrosis is characterized by the presence of fibronectin (FN) isoforms including extra domain A-spliced FN variant (EDA-FN). We investigated the role of EDA-FN in a murine model of PD.
Methods
Male wild-type (WT) and EDA-FN knockout (KO) mice were randomized to receive saline (Control Group) or glucose-based PD fluid containing 40 mM methylglyoxal (PDF Group) by intra-peritoneal injection twice daily for 4, 8 and 12 weeks, after which time the parietal peritoneum was harvested to investigate peritoneal membrane histology and expression of mediators of inflammation and fibrosis using a combination of qPCR, Western blot analysis and cytochemical staining. Human peritoneal mesothelial cells were isolated from omentum to investigate the mechanism of EDA-FN induction.
Results
PDF-treated WT mice developed submesothelial thickening after 12 weeks compared to saline-treated mice, accompanied by a marked influx of immune cells and mesothelial cell denudation. EDA-FN gene expression was increased in the peritoneal membrane of PDF-treated mice (1.00 ± 0.13 vs 15.46 ± 9.83 arbitrary units, saline vs PDF, p = 0.0095), accompanied by increased gene and/or protein expression of TGF-β1, IL-1β, IL-6, native FN, collagen I and III, α-smooth muscle actin and Adgre1 (F4/80). PDF-induced peritoneal membrane pathology and thickening were markedly reduced in EDA-FN KO mice compared to WT mice, with reduced immune cell infiltration and mediators of inflammation and fibrosis. In cultured mesothelial cells, PDF induced native FN and EDA-FN expression through the synergistic effect of TGF-β1 and IL-1β.
Conclusion
Our data suggest that increased peritoneal EDA-FN expression in PDF-treated mice contributes to peritoneal inflammation and fibrosis in PD.
Funding
- Government Support – Non-U.S.