High Glucose Induces a Hypertrophic, Senescent Mesothelial Cell Phenotype after Long in vivo Exposure

Abstract

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) concentration dialysis solutions resulted in a hypertrophic mesothelial phenotype characterized by increased cell surface area, multinucleation, low proliferative capabilities, reduced cell viability, and enhanced enzymatic activity. These elements that define a senescent population of cells were not related to the pH of the fluid and its osmolality, or to the presence of buffer lactate. The present study was designed to explore the adverse effects of a lactate-free, filter-sterilized, high-D-glucose concentration solution (4.25%) at normal pH and prepared in Hanks’ buffered salt solution after 2 h, 15 and 30 days of once a day intraperitoneal injection. Analysis of our observations indicate that in vivo exposure of the mesothelium to a high-glucose concentration induced a decreased density of the cell population, made up by larger and multinucleated cells, the viability of which was significantly lower than that observed in intact unexposed mice. The prevalence of mitosis 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 main effect of the high-glucose concentration appears to result not from a mechanism of cytotoxicity, but from a substantial change in the life cycle of the exposed cell population, leading to their premature senescence and death in apoptosis. We hypothesize that this outcome may well be mediated by sustained oxidative stress derived from both a reduced production of scavengers, as well as the increased generation of oxygen-reactive species.

Accelerated senescence of human peritoneal mesothelial cells exposed to high glucose: the role of TGF-β1

“…Moreover, our results are in keeping with the observations of Gotloib et al, who detected the appearance of mesothelial cells with the senescent-like phenotype in mice treated chronically with high intraperitoneal load of glucose. 5,27,28 Interestingly, both the in vivo studies and our in vitro experiments showed no significant effect of M, which points to a specific metabolic effect of glucose, unrelated to corresponding hyperosmolality. The peritoneal mesothelium is regarded as a slowly renewing tissue with the basal mitotic activity present in less than 1% cells.…”

“…Therefore, the detrimental impact of high glucose (HG) on mesothelial cells may contribute to the peritoneal membrane dysfunction during dialysis. In a series of experiments, Gotloib et al 4,5 analyzed the imprints of the mesothelium obtained from mice exposed chronically to glucose-containing PDF. They found a significant increase in both the average size of mesothelial cell and the prevalence of very large cells, which together resulted in reduced density of the mesothelial monolayer.…”

Astragalus extract inhibits destruction of gastric cancer cells to mesothelial cells by anti-apoptosis

“…Astragalus injection has only been used in peritoneal dialysis therapy [29] . Studies on Astragalus injection were mainly concentrated on its immunomodulating functions.…”

Vulnerability to oxidative stress and different patterns of senescence in human peritoneal mesothelial cell strains

“…Furthermore, our observations may impact on peritoneal dialysis fluid biocompatibility testing. It has been observed that peritoneal mesothelial cells exposed chronically to dialysis fluids develop a senescence-like phenotype (16). We have previously demonstrated that glucose (a basic component of dialysis solutions) may accelerate the development of senescence features in mesothelial cells, largely by exacerbating oxidative stress (22).…”