3-4-dideoxyglucosone-3-ene and Kidney-Failure--Chronic

Excessive, insufficient, or untimely apoptosis may result in disorders of cell numbers. Peritoneal demesothelization is an example of disease by decreased cell number; untimely leukocyte apoptosis impairs peritoneal defense. Conventional peritoneal dialysis solutions accelerate neutrophil apoptosis. Glucose degradation products such as 3,4-dideoxyglucosone-3-ene (3,4-DGE) decisively contribute to apoptosis induced by these solutions, in both leukocytes and mesothelial cells and in both culture and peritoneal dialysis patients. Pan-caspase inhibition retards neutrophil apoptosis and improves peritoneal clearance of Staphylococcus aureus in animal models. However, regulation of apoptosis in mesothelial cells is more complex than in leukocytes, and caspase inhibitors may not be the optimal drugs to modulate apoptosis in these cells. In this regard, Bax antagonistic peptides protect mesothelial cells from 3,4-DGE. In addition, novel molecular targets have been identified. Short-term modulation of apoptosis may be useful to accelerate recovery and to prevent irreversible peritoneal injury following peritonitis.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Dialysis Solutions; Epithelial Cells; Glycogen Phosphorylase; Humans; Kidney Failure, Chronic; Leukocytes; Peritoneal Dialysis; Peritoneum; Peritonitis; Pyrones

Glucose degradation products (GDPs) are important for the outcome of peritoneal dialysis (PD) treatment. The most cytotoxic GDP found in conventionally manufactured fluids, 3,4-dideoxyglucosone-3-ene (3,4-DGE), may in addition be recruited from 3-deoxyglucosone (3-DG). What happens with the GDPs in the fluid infused into patients during PD is not known. We investigated whether 3,4-DGE and 3-DG in PD fluid can be found in plasma during treatment.. Patients on PD were dialyzed with a conventional PD fluid containing 43 micromol/L 3,4-DGE and 281 micromol/L 3-DG. Parallel experiments were performed in rats and in vitro with human plasma. The rats were dialyzed with a PD fluid containing 100 micromol/L 3,4-DGE and 200 micromol/L 3-DG.. The 3,4-DGE concentration in the peritoneum declined at a much higher rate during the dwell than did the 3-DG concentration. However, 3,4-DGE was not detected in the plasma of patients or of rats during dialysis. The 3-DG concentration in plasma peaked shortly after infusion of fluid into the peritoneal cavity. The 3,4-DGE concentration during experimental incubation in plasma declined rapidly; the 3-DG concentration declined only 10% as rapidly (or less).. During dialysis, 3,4-DGE could not be detected in plasma of either PD patients or rats, presumably because of its high reactivity. On the other hand, 3-DG may pass through the membrane and be detected in the blood.

Topics: Animals; Chromatography, High Pressure Liquid; Dialysis Solutions; Disease Models, Animal; Glycation End Products, Advanced; Glycogen Phosphorylase; Humans; Injections, Intraperitoneal; Kidney Failure, Chronic; Male; Peritoneal Dialysis; Peritoneum; Pyrones; Rats; Rats, Wistar

The mesothelium contributes significantly to the functional, structural and homeostatic properties of the peritoneum. Bioincompatible peritoneal dialysis solutions contribute to mesothelial cell loss during chronic peritoneal dialysis. Cell death has been implicated in mesothelial cell loss, but the molecular mechanisms have not been adequately characterized. We now report the modulation of mesothelial cell death by the glucose degradation product 3,4-dideoxyglucosone-3-ene (3,4-DGE).. Human mesothelial cells were cultured from the effluents of stable dialysis patients. Apoptosis was quantified in cultured mesothelial cells and in peritoneal effluents. Confocal microscopy and inhibitors were used to assess molecular mechanisms.. Peritoneal dialysis solutions with a high content of both glucose and glucose degradation products, but not those with low glucose degradation product content, induced mesothelial cell apoptosis and loss of cell viability in culture and in vivo. 3,4-DGE also induced mesothelial cell apoptosis. Apoptosis induced by peritoneal dialysis solutions and 3,4-DGE was associated with oligomerization of Bax at mitochondria and caspase activation. Bax antagonism prevented caspase activation, apoptosis and cell death. The pancaspase inhibitor zVAD was also protective.. 3,4-DGE and peritoneal dialysis solutions with a high content in glucose degradation products induce mesothelial cell apoptosis by a Bax-dependent mechanism. This could contribute to chronic demesothelization in peritoneal dialysis.

Topics: Aged; Apoptosis; bcl-2-Associated X Protein; Caspases; Cell Death; Cells, Cultured; Dialysis Solutions; Epithelium; Female; Glucose; Humans; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Peritoneum; Pyrones

Heat-sterilized, single-chambered, glucose-containing peritoneal dialysis solutions promote neutrophil apoptosis and impair the peritoneal antibacterial response. It has been proposed that glucose degradation products may be responsible for this effect. However, the precise contribution of individual glucose degradation products had not been addressed.. The effect of individual glucose degradation products on apoptosis in cultured human neutrophils and peripheral blood mononuclear cells was studied.. Peritoneal dialysis solutions with a high content of both glucose and glucose degradation products accelerated neutrophil and mononuclear cell apoptosis. Among the different glucose degradation products, 3,4-di-deoxyglucosone-3-ene (3,4-DGE) accelerated apoptosis in neutrophils and peripheral blood mononuclear cells at concentrations (25 micromol/L) in the range found in heat-sterilized, single-chambered, 4.25% glucose peritoneal dialysis fluids. Apoptosis induced by 3,4-DGE was caspase-dependent and could be prevented by the broad-spectrum caspase inhibitor benzyloxycarbonyl-Val-Ala-DL-Asp-fluoromethylketone (zVAD-fmk). By contrast, no cytotoxicity was observed following the addition of methylglyoxal, acetaldehyde, formaldehyde, or 3-deoxyglucosone at concentrations found in peritoneal dialysis solutions.. 3,4-DGE appears to be the main proapoptotic factor in high glucose peritoneal dialysis solutions. 3,4-DGE may impair peritoneal defenses by accelerating leukocyte apoptosis.

Topics: Apoptosis; Caspases; Cells, Cultured; Dialysis Solutions; Glucose; Humans; In Vitro Techniques; Kidney Failure, Chronic; Neutrophils; Peritoneal Dialysis; Peritonitis; Pyrones