The triggering of human peritoneal mesothelial cell apoptosis and oncosis by glucose and glycoxydation products

Background. Peritoneal dialysis fluids (PDFs) have been shown to alter mesothelial cell functions. To further determine the mechanisms involved, we investigated the effects of glucose, glucose degradation products (GDPs) and advanced glycation end products (AGEs) on the inhibition of human peritoneal mesothelial cell (HPMC) proliferation and the induction of apoptosis and oncosis. Methods. Four PDF solutions, heat-sterilized dextrose-lactate, filtered dextrose-lactate and heat-sterilized dextrose-bicarbonate-lactate, each containing 15 or 45 g/l glucose, and heat-sterilized icodextrin-lactate, containing 75 g/l icodextrin, were tested. In addition, we analysed the independent and synergistic effects of two glucose compounds, i.e. 3-deoxyglucosone (3-DG), a major GDP, and New-epsilon(carboxymethyl)-lysine (CML), a high-affinity AGE receptor (RAGE) ligand on HPMC viability. Cell proliferation was measured by methyl-[H-3]thymidine incorporation. Oncosis was quantified by nuclear propidium iodide (PI) DNA-intercalating capability, and apoptosis by the decrease in mitochondrial transmembrane potential (A m). Results. It was found that heat-sterilized dextroselactate inhibited HPMC proliferation to a greater extent than filtered dextrose -lactate, heat-sterilized dextrose-bicarbonate-lactate, or heat-sterilized icodextrin-lactate (P < 0.00 1). Compared to filtered dextroselactate, heat-sterilized dextro se- lactate induced a significantly greater degree of apoptosis (P<0.05) and oncosis (P < 0.01). Glucose-induced cell death and anti-proliferative activity were significantly potentiated by the action of 3-DG or CML-albumin. By blocking the AGE-RAGE interaction recombinant soluble-RAGE reduced the PDF-induced inhibitory effect on cell proliferation (P<0.001) and apoptosis (P<0.05). Conclusion. Heat-sterilized PDFs that contain high glucose concentrations and GDPs, which are AGE precursors, reduce cell proliferation, induce mesothelial cell apoptosis and oncosis, and may be involved in peritoneal damage. PDFs containing lower glucose derivative products are more biocompatible.