γ-Tocotrienol Protects against Mitochondrial Dysfunction, Energy Deficits, Morphological Damage, and Decreases in Renal Functions after Renal Ischemia

Abstract

Ischemia-induced mitochondrial dysfunction and ATP depletion in the kidney result in disruption of primary functions and acute injury of the kidney. This study tested whether γ-tocotrienol (GTT), a member of the vitamin E family, protects mitochondrial function, reduces ATP deficits, and improves renal functions and survival after ischemia/reperfusion injury. Vehicle or GTT (200 mg/kg) were administered to mice 12 h before bilateral kidney ischemia, and endpoints were assessed at different timepoints of reperfusion. GTT treatment reduced decreases in state 3 respiration and accelerated recovery of this function after ischemia. GTT prevented decreases in activities of complexes I and III of the respiratory chain, and blocked ischemia-induced decreases in F0F1-ATPase activity and ATP content in renal cortical tissue. GTT improved renal morphology at 72 h after ischemia, reduced numbers of necrotic proximal tubular and inflammatory cells, and enhanced tubular regeneration. GTT treatment ameliorated increases in plasma creatinine levels and accelerated recovery of creatinine levels after ischemia. Lastly, 89% of mice receiving GTT and 70% of those receiving vehicle survived ischemia. Conclusions: Our data show novel observations that GTT administration improves mitochondrial respiration, prevents ATP deficits, promotes tubular regeneration, ameliorates decreases in renal functions, and increases survival after acute kidney injury in mice.

Comprehensive overview of the role of mitochondrial dysfunction in the pathogenesis of acute kidney ischemia-reperfusion injury: a narrative review

“…Notably, the ROS-responsive chitosan-SS31 prodrug, which has antioxidant properties, alleviated ROS levels and improved kidney function in a murine model of IR injury [ 69 ]. As a member of the vitamin E family, γ-tocotrienol improved mitochondrial function, promoted tubular regeneration, and ameliorated kidney functions in a murine IR model [ 70 ]. Treprostinil, a U.S. Food and Drug Administration-approved prostacyclin (PGI2) analog, can improve mitochondrial function and reduce IR injury by a PGC-1α- and SIRT-dependent mechanism [ 71 ].…”

Focus on Mitochondrial Respiratory Chain: Potential Therapeutic Target for Chronic Renal Failure

“…Preventive administration of the member of the vitamin E family, γ-tocotrienol, could effectively prevent the decrease in the activity of complexes I, III, and F 0 F 1 -ATPase after ischemia/reperfusion injury, preserve ATP levels in the renal cortex, and alleviate renal tubular injury and the post-injury inflammatory response [186]. However, as with curcumin, this drug is still in the stage of preventive administration and lacks verification in CKD models.…”

Tocotrienols Provide Radioprotection to Multiple Organ Systems through Complementary Mechanisms of Antioxidant and Signaling Effects

“…Mitochondrial bioenergetic health is central to the pathophysiology underlying most types of chronic disease and acute injury. During stressors that lead to mitochondrial dysfunction, tocotrienols beneficially modulate the electron transport chain to improve oxidative phosphorylation, mitochondrial membrane potential, and ATP production [59][60][61][62][63][64]. Tocotrienols may also promote mitochondrial biogenesis through their effects on relevant transcription factors such as NRF2.…”