High glucose induces a hypertrophic, senescent mesothelial cell phenotype after long in vivo exposure

Previous studies, done using our mouse model for population analysis of the mesothelium, showed evidence indicating that in vivo, long-term exposure ( up to 30 days) of the peritoneum to high-glucose (4.25% D-glucose) concentr ation dialysis solutions resulted in a hypertrophic mesothelial phenotype c haracterized by increased cell surface area, multinucleation, low prolifera tive capabilities, reduced cell viability, and enhanced enzymatic activity. These elements that define a senescent population of cells were not relate d to the pH of the fluid and its osmolality, or to the presence of buffer l actate. The present study was designed to explore the adverse effects of a lactate-free, filter-sterilized, high-P glucose concentration solution (4.2 5%) at normal pH and prepared in Hanks' buffered salt solution after 2 h, 1 5 and 30 days of once a day intraperitoneal injection. Analysis of our obse rvations indicate that in vivo exposure of the mesothelium to a high-glucos e concentration induced a decreased density of the cell population, made up by larger and multinucleated cells, the viability of which was significant ly lower than that observed in intact unexposed mice. The prevalence of mit osis showed an early and short-lived acceleration (up to 3 days), followed by values near zero during the rest of the follow-up period. So far, the ma in effect of the high-glucose concentration appears to result not from a me chanism of cytotoxicity, but from a substantial change in the life cycle of the exposed cell population, leading to their premature senescence and dea th in apoptosis. We hypothesize that this outcome may well be mediated by s ustained oxidative stress derived from both a reduced production of scaveng ers, as well as the increased generation of oxygen-reactive species.