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γ‐Tocotrienol Protects Against Mitochondrial Dysfunction, Energy Deficits, Tissue Damage, and Decreases in Renal Functions After Renal Ischemia.
Author(s) -
Nowak Grazyna,
Megyesi Judit,
Che Yingni
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.03488
Subject(s) - ischemia , renal ischemia , kidney , mitochondrion , medicine , renal function , acute kidney injury , endocrinology , necrosis , pharmacology , chemistry , reperfusion injury , biochemistry
Renal ischemia is encountered in multiple clinical settings and frequently results in acute kidney injury (AKI) due to insufficient energy production to sustain renal functions. Ischemia‐induced mitochondrial dysfunction and ATP depletion result in disruption of the primary functions of the kidney in many affected hospitalized patients who suffer AKI, but are left without an effective treatment. This study tested whether γ‐tocotrienol (GT3), a member of the vitamin E family, promotes mitochondrial function, reduces ATP deficits and tissue damage, improves renal functions, and diminishes AKI after renal ischemia/reperfusion injury in mice. Mice were treated with vehicle or GT3 (200 mg/kg) 15h before or immediately after bilateral kidney ischemia, and end points were assessed in kidneys harvested at 24h, 72h, and 168h of reperfusion. GT3 treatment prior to and after ischemia reduced decreases in mitochondrial state 3 respiration and accelerated recovery of this function after ischemia. GT3 prevented the decreases in activities of NADH:Ubiquinone Oxidoreductase (complex I) and Ubiquinol:Cytochrome c Oxidoreductase (complex III) of the mitochondrial electron transport chain regardless of whether it was administered before or after ischemia. GT3 treatment also blocked ischemia‐induced decreases in ATP synthase (F O F 1 ‐ATPase) activity and ATP content in renal cortical tissue. Furthermore, GT3 reduced renal tissue injury (decreased renal tubular necrosis and cast formation) and accelerated morphological regeneration of renal proximal tubules after ischemia. Kidneys of mice treated with GT3 displayed morphological improvements at 72h after ischemia by exhibiting fewer necrotic proximal tubules and inflammatory cells, while demonstrating increased tubular regeneration. GT3 treatment ameliorated increases in plasma creatinine levels and accelerated recovery of renal function after ischemia. Lastly, 89% of mice receiving GT3 and 70% of those receiving vehicle survived 72h after ischemia. In conclusions, GT3 administration improves mitochondrial respiratory functions and activity of F O F 1 ‐ATPase, and prevents ATP deficits in ischemic kidneys. This is associated with improved kidney morphology, ameliorated decreases in renal functions, and increased survival after AKI. Support or Funding Information This research was supported by Arkansas Science & Technology Authority; Grant 15‐B‐27.