Glycogen synthase kinase-3 in peritoneal dialysis failure

Peritoneal dialysis (PD) is the most frequently applied dialysis modality in children. Unfortunately, the non- physiological components of the dialysis fluid such as high glucose concentration and the presence of glucose- degradation products (GDPs) and advanced glycation end products (AGEs) that are formed due to heat-sterilization often lead to the injury of peritoneal mesothelial cells resulting in the loss of membrane integrity and thus, technical failure of PD. Pathological changes in the peritoneum are associated with increased stress of peritoneal mesothelial cells. Previous research on PD has almost exclusively focused on the acute stressful effects of PD fluids where cytoprotective heat-shock proteins (HSPs) were shown to be up-regulated in mesothelial cells to counteract toxic injury. Unfortunately, acute PD models do not sufficiently model the clinical course of dialysis and therefore, more sophisticated exposure models should be used. The Aufricht group has recently demonstrated that chronic exposure of mesothelial cells to PD fluids results in blunted expression of HSPs, however the underlying signaling mechanisms have not yet been explored. HSPs belong to the main defense mechanisms of cells against various stress factors and therefore, they represent an attractive target of intervention to prolong and improve PD efficacy. A particularly attractive target is represented by glycogen synthase kinase (GSK)-3ß, a protein kinase which is a central regulator of cell stress and survival and known to be influenced by high glucose and GDPs. GSK-3ß inactivates several target molecules among which the HSP inducing heat-shock factor-1 (HSF-1) has recently gained more attention. In this study, we aim to assess the role of GSK-3ß in mesothelial cells and its impact on HSF-1, HSP expression and survival of mesothelial cells following chronic in vitro exposure to glucose based PDF with or without high GDP content due to heat- or filter-sterilization.