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 ␥-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 ␣-tocopherol (AT). Reactive oxygen species (ROS) production increased 300% in TBHP-injured RPTCs. State 3 respiration, oligomycinsensitive respiration, and respiratory control ratio (RCR) decreased 50, 63, and 47%, respectively. The number of RPTCs with polarized mitochondria decreased 54%. F 0 F 1 -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 oligomycinsensitive respirations and F 0 F 1 -ATPase activity, and maintained RCR and mitochondrial membrane potential (⌬⌿ 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, ⌬⌿ m , and F 0 F 1 -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.

Protein kinase C-α activation promotes recovery of mitochondrial function and cell survival following oxidant injury in renal cells

“…The carboxy-derivative of fluorescein, carboxy-H2DCFDA, was used to assess oxidant generation in RPTC as described previously (27). RPTC were loaded with 5 M carboxy-H2DCFDA followed by treatment with TBHP for 50 min.…”

Protective effect of vitamin E against acute kidney injury

“…For example, a kidney injury can increase sympathetic nervous system activity and blood pressure as mediated by increased ROS in brain nuclei, but a vitamin E-fortified diet is able to mitigate the formation of ROS in the brain, and then, the antioxidants seem to be beneficial for managing hypertension caused by renal injury and increased sympathetic nervous system activity [50]. In addition, vitamin E also has the ability to protect the renal proximal tubular cells against injury in vitro by decreasing ROS production and by further preventing cell lysis, maintaining adenosine triphosphate levels, and improving mitochondrial respiration, coupling, and membrane potential [51]. Therefore, vitamin E is therapeutically valuable for preventing renal injuries associated with ROS.…”

Mitochondrial Free Radicals, Antioxidants, Nutrient Substances, and Chronic Hepatitis C

“…Increased free radicals generated by damaged mitochondria can cause oxidative damage and a significant decline in metabolic processes; increase the mitochondrial membrane potential; impair the flow of electrons along the ETC; decrease mitochondrial membrane fluidity; decrease respiratory control ratios and cellular oxygen consumption; oxidate cardiolipin (a phospholipid and located at both the inner and outer membranes); deplete cytochrome c; induce cellular calcium (Ca +2 ) dyshomeostasis; and produce high levels of unwanted oxidants (Mecocci et al, 1997;Petrosillo et al, 2003;Mei et al, 2012;Nowak et al, 2012). The inevitable by-products of oxidative phosphorylation can modify and damage mtDNA, proteins, lipid, and matrix components in the mitochondria, as well as deplete cellular antioxidants, which all lead to cell death (Marchi et al, 2012).…”