N-3 PUFAs reduce oxidative stress in ESRD patients on maintenance HD by inhibiting 5-lipoxygenase activity.
Reactive oxygen species formation and release of pro-inflammatory/pro-atherogenic cytokines, that is, interleukin 1-beta and tumor necrosis factor-alpha, need the activation of the arachidonic acid cascade via the enzyme 5-lipoxygenase (5-Lox). 5-Lox activity and expression are significantly increased in peripheral blood mononuclear cells (PBMCs) of end-stage renal disease (ESRD) patients on maintenance hemodialysis (HD). Diets enriched with n-3 polyunsaturated fatty acids (PUFAs) (omega-3) have been associated to a lower incidence of coronary heart disease (CHD) and a reduction in atherosclerotic lesions. Omega-3 may interfere with the arachidonic acid cascade by inhibiting 5-Lox. Lipid peroxidation, leukotriene B(4) (LTB(4)) production, 5-Lox activity and expression were investigated in PBMC isolated from ESRD patients under maintenance HD before and after a 3-month oral supplementation with omega-3 at a daily dose of 2700 mg of n-3 PUFAs at the average eicosapentaenoic acid/docosaesaenoic acid ratio of 1.2 and finally after a further 3-month washout with no omega-3 supplementation. PBMCs from non-uremic volunteers were also investigated for comparison to normal parameters. Administration of omega-3 reduced significantly lipid peroxidation (P < 0.0001), LTB(4) synthesis (P < 0.0001) and 5-Lox activity (P < 0.0001), with no effect on 5-Lox protein expression. After the 3-month washout, all parameters were comparable to those observed before treatment. Our results resemble those obtained after oral administration of vitamin E and are consistent with a reversible, dose-dependent inhibition of 5-Lox by omega-3. Upregulation of 5-Lox may also be related to the increased mitochondrial damage and apoptosis of PBMCs observed in ESRD patients compared to non-uremic controls. Omega-3 may thus protect PBMCs of ESRD patients against oxidative stress.
Section of Nephrology, Department of Biopathology and Imaging Techniques, Tor Vergata University, Rome, Italy. mmaccarrone@unite.it
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Taccone-Gallucci
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Manca-di-Villahermosa
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Battistini
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Stuffler
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Tedesco
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Maccarrone
D000368:Aged; D017209:Apoptosis; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D015525:Fatty Acids, Omega-3 / Q000627:therapeutic use*; D015870:Gene Expression; D006801:Humans; D007676:Kidney Failure, Chronic / Q000188:drug therapy* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology; D007975:Leukotriene B4 / Q000032:analysis; D015227:Lipid Peroxidation / Q000187:drug effects; D016859:Lipoxygenase Inhibitors; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects*; D006435:Renal Dialysis
D015525:Fatty Acids, Omega-3; D016859:Lipoxygenase Inhibitors; D007975:Leukotriene B4; D001094:Arachidonate 5-Lipoxygenase