Methylglyoxal: a stimulus to neutrophil oxygen radical production in chronic renal failure?
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 H(2)O(2) and O(-)(2) 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 H(2)O(2) production and basal and formyl-methionyl-leucyl-phenylalanine-stimulated O(-)(2) 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.
Ward
Richard A
RA
Department of Medicine, University of Louisville, Louisville, KY 40202-1718, USA. richard.ward@kdp.louisville.edu
McLeish
Kenneth R
KR
D005089:Exocytosis / Q000187:drug effects; D006801:Humans; D007676:Kidney Failure, Chronic / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism*; D011765:Pyruvaldehyde / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016897:Respiratory Burst; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D017382:Reactive Oxygen Species; D011765:Pyruvaldehyde; D048051:p38 Mitogen-Activated Protein Kinases