5-Lipoxygenase-mediated mitochondrial damage and apoptosis of mononuclear cells in ESRD patients.
BACKGROUND
5-Lipoxygenase activity is enhanced in peripheral blood mononuclear cells (PBMC) from end-stage renal disease (ESRD) patients on maintenance hemodialysis (HD), leading to lipoperoxidation and reactive oxygen species formation. These effects are prevented by vitamin E, which inhibits 5-lipoxygenase activity. The present study was designed to test the possibility that 5-lipoxygenase activation might cause mitochondrial damage and cytochrome c release, ultimately leading PBMC to apoptosis.


METHODS
Apoptosis, mitochondrial uncoupling, and cytochrome c release were investigated in PBMC from 16 healthy volunteers and 16 ESRD patients on maintenance HD with cuprammonium rayon (CL-S) membranes in a two-step crossover study: after a four-week treatment with vitamin E-coated cuprammonium rayon (CL-E) membranes, and again after a four-week treatment with oral vitamin E.


RESULTS
Compared to healthy controls, PBMC from ESRD patients showed an approximately threefold increase in mitochondrial uncoupling and cytochrome c release (within 4 and 8 hours, respectively), followed by an approximately threefold increase in apoptotic body formation (within 48 hours). Regardless of the administration route, vitamin E reduced mitochondrial uncoupling, cytochrome c release and apoptosis of mononuclear cells, as did the 5-lipoxygenase inhibitor eicosatetraynoic acid. Conversely, the cyclooxygenase inhibitor indomethacin was ineffective.


CONCLUSIONS
Reported data suggest that the 5-lipoxygenase branch of the arachidonate cascade is only responsible for mitochondrial disruption and apoptosis of PBMC of ESRD patients, and that vitamin E may be helpful in the control of oxidative stress-related disease in these subjects, independent of the administration route.
Maccarrone
Mauro
M
Department of Biomedical Sciences, University of Teramo, Italy. Maccarrone@vet.unite.it
Taccone-Gallucci
Massimo
M
Finazzi-Agrò
Alessandro
A
D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D003574:Cytochrome c Group / Q000378:metabolism; D003956:Dialysis / Q000379:methods; D006801:Humans; D066298:In Vitro Techniques; D007676:Kidney Failure, Chronic / Q000276:immunology / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress / Q000276:immunology; D014810:Vitamin E / Q000494:pharmacology
D000975:Antioxidants; D003574:Cytochrome c Group; D014810:Vitamin E; D001094:Arachidonate 5-Lipoxygenase