Abstract: SA-PO940
Hyaluronan Generated During Peritoneal Dialysis Does Not Drive Fibrosis, but Regulates Inflammatory Cell Recruitment Through Differential Hyaluronan Synthase (HAS) Expression
Session Information
- Dialysis: Peritoneal Dialysis - III
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Dialysis
- 703 Dialysis: Peritoneal Dialysis
Authors
- Williams, Aled P., Wales Kidney Research Unit, Cardiff, United Kingdom
- Midgley, Adam C., Nankai University, Tianjin, China
- Phillips, Aled O., Wales Kidney Research Unit, Cardiff, United Kingdom
- Steadman, Robert, Wales Kidney Research Unit, Cardiff, United Kingdom
- Bowen, Timothy, Wales Kidney Research Unit, Cardiff, United Kingdom
- Fraser, Donald, Wales Kidney Research Unit, Cardiff, United Kingdom
- Meran, Soma, Wales Kidney Research Unit, Cardiff, United Kingdom
Background
Peritoneal membrane dysfunction is a key determinant of Peritoneal Dialysis (PD) failure, and is associated with repeated episodes of peritonitis and exposure to bio-incompatible dialysis solutions. TGF-β1-driven transdifferentiation of mesothelial cells to myofibroblasts through mesothelial to mesenchymal transition (MMT) underlies peritoneal membrane dysfunction and ultimately peritoneal fibrosis. In solid organ fibrosis (kidneys & lungs), pro-fibrotic cell differentiation is driven by changes in synthesis and macromolecular organisation of the matrix polysaccharide hyaluronan (HA). In this work, we determine whether factors that regulate HA synthesis in the peritoneum have a the role in driving peritoneal inflammation and in the prevention/reversal of fibrosis
Methods
In-vitro studies were performed on human peritoneal mesothelial cells and ex-vivo PD effluent from patients with peritonitis. Genetic and histological analysis of peritoneal membranes from a murine model of peritoneal inflammation (live attenuated staphylococcus epidermidis induced peritonitis) were utilised in-vivo
Results
Patients with PD peritonitis had significantly increased HA concentrations day-1 after developing acute bacterial peritonitis compared to non-infected patients. TGF-β1-driven MMT in primary human mesothelial cells significantly increased extracellular HA generation, predominantly driven by Hyaluronan Synthase-1 (HAS1) isoenzyme expression. In contrast to kidney and lung fibrosis this increased HA was not causally involved in driving MMT. Instead, HAS1 in peritoneal tissues and mesothelial cells was associated with enhanced leukocyte recruitment and activation in the peritoneum. Blockade of HAS1 driven HA synthesis in mice led to delayed neutrophil clearance and monocyte recruitment indicating a delayed inflammatory response
Conclusion
In contrast to solid-organ fibrosis where HA seems to have an important role in driving fibrosis through a HAS2 dependent phenotype, TGF-β1 driven MMT in mesothelial cells generates HA that is not involved in peritoneal fibrosis. HAS1 generated by mesothelial cells appears to be involved in regulating the acute inflammatory response and may be involved in reparative processes that limit fibrosis in the peritoneum