| Summary: | Morphological changes including fibrosis, vascular degeneration and loss of mesothelium occur to the peritoneal membrane during peritoneal dialysis. The loss of mesothelium is thought to effect peritoneal homeostasis and host defence, as these cells play a pivotal role in these organs response to inflammation. Cancer antigen 125 (CA125), a mucilaginous high molecular weight glycoprotein, has been used as a marker of peritoneal mesothelial cells mass/turnover and membrane functional integrity in peritoneal dialysis patients. The use of new more biocompatible dialysis solutions is associated with an increase in CA125 effluent concentration, however it's precise molecular nature, function and regulation is poorly defined. This study investigates the transcriptional mechanisms regulating CA125 expression in human peritoneal mesothelial cells as well as CA125's regulation in response to inflammation. Additionally, CA125's function in the process of mesothelial cell repair is examined using a novel mesothelial wound healing system. These investigations have: Successfully reconstructed the genomic structure of CA125 and characterised its proximal promoter region. Demonstrated regulation of CA125 cell surface expression and shedding in response to IL-1 p and IL-6 trans-signalling. Shown the retardation of human peritoneal mesothelial cell CA125 shedding in response to high levels of glucose degradation products present within peritoneal dialysis fluids. Shown the improved wound healing of mesothelial cells in response to elevated CA125 levels. These investigations have clarified existing discrepancies regarding CA125 regulation during inflammation by demonstrating its altered expression at the cell surface, in response to inflammatory mediators. Additionally, this work has linked clinical Observations regarding CA125 effluent levels during peritoneal dialysis to a potential role of CA125 in wound healing of the mesothelium.
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