title: γ-Tocotrienol protects against mitochondrial dysfunction and renal cell death.
abstract: Oxidative stress is a major mechanism of a variety of renal diseases. Tocopherols and tocotrienols are well known antioxidants. This study aimed to determine whether γ-tocotrienol (GT3) protects against mitochondrial dysfunction and renal proximal tubular cell (RPTC) injury caused by oxidants. Primary cultures of RPTCs were injured by using tert-butyl hydroperoxide (TBHP) in the absence and presence of GT3 or α-tocopherol (AT). Reactive oxygen species (ROS) production increased 300% in TBHP-injured RPTCs. State 3 respiration, oligomycin-sensitive respiration, and respiratory control ratio (RCR) decreased 50, 63, and 47%, respectively. The number of RPTCs with polarized mitochondria decreased 54%. F₀F₁-ATPase activity and ATP content decreased 31 and 65%, respectively. Cell lysis increased from 3% in controls to 26 and 52% at 4 and 24 h, respectively, after TBHP exposure. GT3 blocked ROS production, ameliorated decreases in state 3 and oligomycin-sensitive respirations and F₀F₁-ATPase activity, and maintained RCR and mitochondrial membrane potential (ΔΨ(m)) in injured RPTCs. GT3 maintained ATP content, blocked RPTC lysis at 4 h, and reduced it to 13% at 24 h after injury. Treatment with equivalent concentrations of AT did not block ROS production and cell lysis and moderately improved mitochondrial respiration and coupling. This is the first report demonstrating the protective effects of GT3 against RPTC injury by: 1) decreasing production of ROS, 2) improving mitochondrial respiration, coupling, ΔΨ(m), and F₀F₁-ATPase function, 3) maintaining ATP levels, and 4) preventing RPTC lysis. Our data suggest that GT3 is superior to AT in protecting RPTCs against oxidant injury and may prove therapeutically valuable for preventing renal injury associated with oxidative stress.
authors: Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, 4301 West Markham St., MS 522-3, Little Rock, AR 72205, USA. gnowak@uams.edu
authors: Grazyna
authors: G
authors: Nowak
authors: Diana
authors: D
authors: Bakajsova
authors: Corey
authors: C
authors: Hayes
authors: Martin
authors: M
authors: Hauer-Jensen
authors: Cesar M
authors: CM
authors: Compadre
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D019069:Cell Respiration / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002839:Chromans / Q000378:metabolism / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D007687:Kidney Tubules, Proximal / Q000166:cytology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D009840:Oligomycins / Q000494:pharmacology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010101:Oxygen Consumption / Q000187:drug effects; D006180:Proton-Translocating ATPases / Q000378:metabolism; D011817:Rabbits; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D024502:alpha-Tocopherol / Q000494:pharmacology; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
chemical_list: D002839:Chromans; D009840:Oligomycins; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D014810:Vitamin E; C013649:plastochromanol 8; D000255:Adenosine Triphosphate; D020122:tert-Butylhydroperoxide; D007770:L-Lactate Dehydrogenase; D006180:Proton-Translocating ATPases; D024502:alpha-Tocopherol