title: Acceleration of neutrophil apoptosis by glucose-containing peritoneal dialysis solutions: role of caspases.
abstract: Commercial, glucose-containing peritoneal dialysis (PD) solutions have deleterious effects on leukocytes and mesothelial cells that contribute to an impaired peritoneal defense. However, the molecular mechanisms of these deleterious effects are poorly understood. The effect of PD solutions on neutrophil viability, the molecular mechanisms of cell death, its functional consequences, and the possibilities for pharmacologic modulation have now been studied. The effect of newly available, bicarbonate-buffered PD solutions were further investigated. Lactate-buffered, glucose-containing PD solutions increased the apoptosis rate of cultured neutrophils (control media versus 4.25% glucose PD solution: 31 +/- 3% versus 52 +/- 3% apoptosis at 24 h, P < 0.001). Bicarbonate-buffered, 4.25% glucose-containing PD solutions with low concentration of glucose degradation products did not increase the rate of apoptosis. Apoptosis induced by lactate-buffered, 4.25% glucose PD solutions was not related to hyperosmolality or acidic pH and was not reproduced by increasing the glucose concentration by the addition of glucose to a commercial, lactate-buffered fluid. Neutrophil apoptosis was associated with caspase-3 activation. Inhibition of caspase-3 by the use of the caspase-3 inhibitor acetyl-Asp-Glu-Val-Asp-fmk or the broad-spectrum caspase inhibitor benzyloxycarbonyl-Val-Ala-DL-Asp-fluoromethylketone (zVAD-fmk) prevented features of apoptosis, such as morphologic changes, internucleosomal DNA degradation, and the appearance of hypodiploid cells and increased the number of viable, trypan blue-excluding neutrophils. Furthermore, zVAD-fmk increased neutrophil phagocytosis of bacteria. However, the caspase-1 inhibitor acetyl-Tyr-Val-Ala-Asp-aldehyde did not prevent cell death. These data suggest that unidentified components in commercial, lactate-buffered, high-glucose PD fluid accelerate the rate of neutrophil apoptosis. Glucose degradation products may be such unidentified components. Acceleration of neutrophil apoptosis may contribute to the impaired local defense system of patients undergoing PD.
authors.affiliation: Unidad de Dialisis, Fundacion Jimenez Diaz, Universidad Autónoma, Madrid, Spain.
authors.forename: Marina Penélope
authors.initials: MP
authors.lastname: Catalan
authors.affiliation: Unidad de Dialisis, Fundacion Jimenez Diaz, Universidad Autónoma, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Reyero
authors.affiliation: Unidad de Dialisis, Fundacion Jimenez Diaz, Universidad Autónoma, Madrid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Egido
authors.affiliation: Unidad de Dialisis, Fundacion Jimenez Diaz, Universidad Autónoma, Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002021:Buffers; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D015314:Dialysis Solutions / Q000494:pharmacology*; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D019344:Lactic Acid; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D010530:Peritoneal Dialysis; D013997:Time Factors
chemical_list: D002021:Buffers; D061945:Caspase Inhibitors; D015314:Dialysis Solutions; D004791:Enzyme Inhibitors; D019344:Lactic Acid; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D005947:Glucose