5-Lipoxygenase-mediated mitochondrial damage and apoptosis of mononuclear cells in ESRD patients.

Abstract

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.

• Authors: Mauro Maccarrone, Massimo Taccone-Gallucci, Alessandro Finazzi-Agrò
• Journal: Kidney international. Supplement (Kidney Int Suppl) Issue 84 Pg. S33-6 (May 2003) ISSN: 0098-6577 [Print] United States
• PMID: 12694304 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Cytochrome c Group
• Vitamin E
• Arachidonate 5-Lipoxygenase

Topics

• Antioxidants (pharmacology)
• Apoptosis (physiology)
• Arachidonate 5-Lipoxygenase (metabolism)
• Cytochrome c Group (metabolism)
• Dialysis (methods)
• Humans
• In Vitro Techniques
• Kidney Failure, Chronic (immunology, metabolism)
• Leukocytes, Mononuclear (cytology, drug effects, enzymology)
• Middle Aged
• Mitochondria (metabolism)
• Oxidative Stress (immunology)
• Vitamin E (pharmacology)