Methylglyoxal: a stimulus to neutrophil oxygen radical production in chronic renal failure?

• Published in: Nephrology, dialysis, transplantation dialysis, transplantation, 2004-07, Vol.19 (7), p.1702-1707
• Main Authors: Ward, Richard A., McLeish, Kenneth R.
• Format: Article
• Language: English
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Biological and medical sciences; Emergency and intensive care: renal failure. Dialysis management; Exocytosis - drug effects; Humans; Intensive care medicine; Kidney Failure, Chronic - metabolism; Medical sciences; methylglyoxal; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; neutrophil; Neutrophils - drug effects; Neutrophils - metabolism; oxidant stress; p38 Mitogen-Activated Protein Kinases - physiology; Pyruvaldehyde - pharmacology; reactive oxygen species; Reactive Oxygen Species - metabolism; Renal failure; Respiratory Burst; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Surgery of the urinary system; uraemia
• ISSN: 0931-0509; 1460-2385
• DOI: 10.1093/ndt/gfh271

Background. Chronic renal failure is characterized by oxidant stress, resulting in part from increased reactive oxygen species production by neutrophils. Plasma concentrations of methylglyoxal are increased in uraemia. Methylglyoxal activates p38 mitogen-activated protein kinase (MAPK) in endothelial cells. Activation of p38 MAPK in neutrophils enhances reactive oxygen species production through exocytosis of intracellular storage granules. We tested the hypothesis that methylglyoxal enhances reactive oxygen species production by activating p38 MAPK in neutrophils. Methods. Neutrophils were exposed to methylglyoxal in vitro. Activation of p38 MAPK was determined by immunoblot analysis. Exocytosis was determined by measuring plasma membrane expression of CD35 and CD66b, specific markers of secretory vesicles and specific granules, respectively. Reactive oxygen species production was determined by measuring H2O2 and \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{O}^{{-}}_{2}\) \end{document} production. Results. Methylglyoxal activated p38 MAPK and caused dose-dependent increases in CD35 and CD66b expression, which were blocked by the methylglyoxal scavenger, aminoguanidine, or the p38 MAPK inhibitor, SB203580. Methylglyoxal caused dose-dependent increases in basal and Staphylococcus aureus-stimulated H2O2 production and basal and formyl-methionyl-leucyl-phenylalanine-stimulated \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{O}^{{-}}_{2}\) \end{document} production. Enhancement of reactive oxygen species production was blocked by aminoguanidine and SB203580. Conclusions. Methylglyoxal enhances reactive oxygen species production in neutrophils through a process involving p38 MAPK-dependent exocytosis of intracellular storage granules. These findings, together with the observation that methylglyoxal concentrations are increased in renal failure, suggest a possible role for methylglyoxal as a uraemic toxin that contributes to the oxidant stress associated with renal failure.