Peritoneal Dialysis (PD) offers many advantages as a modality choice in ESRD compared to haemodialysis. In particular, it better preserves residual renal function, allows patients greater autonomy and is associated with reduced costs. However longevity of treatment with PD is limited because the constant exposure of the peritoneal membrane to bio-incompatible PD solutions, and repeated episodes of PD peritonitis cause peritoneal membrane damage and fibrosis; leading to inadequate small solute clearance and ultrafiltration failure.
An important driver of mesothelial thickening and fibrosis of the peritoneal membrane is the transdifferentiation of mesothelial cells to myofibroblasts through the process of mesothelial to mesenchymal transition (MMT). In the mesothelium this process is largely driven by the pro-fibrotic cytokine Transforming Growth Factor-(TGF)-b1. TGF-b1 has been shown to promote myofibroblast persistence in other tissue and organ fibrosis through promoting fibroblast to myofibroblast differentiation and epithelial to mesenchymal transition (EMT). In our studies, we have previously delineated these two latter processes and identified that TGF-b1-driven fibroblast to myofibroblast differentiation and EMT are dependent on changes in synthesis and macromolecular organisation of the matrix polysaccharide hyaluronan (HA). Conversely, Bone morphogenic protein-7 (BMP-7), a member of the TGF-b superfamily, has been shown to prevent and reverse renal fibrosis of the kidneys and fibrosis in other tissues including the liver and lung. Our group has shown in our cell systems, that BMP-7 antagonises the effects of TGF-b1 through increased CD44 variant isoform expression of CD44v7/8 leading to dissolution and internalisation of the HA coat.
HA is a connective tissue glycosaminoglycans, which demonstrates increased expression in numerous fibrotic diseases. It is synthesized by the HA Synthase enzymes (HAS1, HAS2 & HAS3) and is broken down by the Hyaluronidase enzymes (predominanty Hyal1 & Hyal2). Not only its increased synthesis, but its assembly and manner of interaction with cell-surface receptors (CD44) and HA binding proteins (hyaladherins) has been shown to influence many cellular processes and disease states. We have previously shown that HA in various contexts can both promote and prevent pro-fibrotic phenotypes. However the role of HA in driving MMT in the mesothelium has not yet been investigated. Moreover, although increased expression of HA in the mesothelium and in PD effluent of patients with PD peritonitis and PD failure has been detected, the role of HA matrix in peritoneal infection, inflammation and fibrosis is not yet understood.
1. Characterisation of HA Matrix Components Present in Mesothelial Cells and their Alterations in Response to MMT
2. Investigate the Mechanism underlying the lack of BMP-7 response to TGF-β1-Driven MMT in Mesothelial Cells
3. Understand the role of HA matrix components in peritoneal infection, inflammation and fibrosis
Dr Aled Williams