title: Deletion of protein kinase C-ε attenuates mitochondrial dysfunction and ameliorates ischemic renal injury.
abstract: Previously, we documented that activation of protein kinase C-ε (PKC-ε) mediates mitochondrial dysfunction in cultured renal proximal tubule cells (RPTC). This study tested whether deletion of PKC-ε decreases dysfunction of renal cortical mitochondria and improves kidney function after renal ischemia. PKC-ε levels in mitochondria of ischemic kidneys increased 24 h after ischemia. Complex I- and complex II-coupled state 3 respirations were reduced 44 and 27%, respectively, in wild-type (WT) but unchanged and increased in PKC-ε-deficient (KO) mice after ischemia. Respiratory control ratio coupled to glutamate/malate oxidation decreased 50% in WT but not in KO mice. Activities of complexes I, III, and IV were decreased 59, 89, and 61%, respectively, in WT but not in KO ischemic kidneys. Proteomics revealed increases in levels of ATP synthase (α-subunit), complexes I and III, cytochrome oxidase, α-ketoglutarate dehydrogenase, and thioredoxin-dependent peroxide reductase after ischemia in KO but not in WT animals. PKC-ε deletion prevented ischemia-induced increases in oxidant production. Plasma creatinine levels increased 12-fold in WT and 3-fold in KO ischemic mice. PKC-ε deletion reduced tubular necrosis, brush border loss, and distal segment damage in ischemic kidneys. PKC-ε activation in hypoxic RPTC in primary culture exacerbated, whereas PKC-ε inhibition reduced, decreases in: 1) complex I- and complex II-coupled state 3 respirations and 2) activities of complexes I, III, and IV. We conclude that PKC-ε activation mediates 1) dysfunction of complexes I and III of the respiratory chain, 2) oxidant production, 3) morphological damage to the kidney, and 4) decreases in renal functions after ischemia.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas; and gnowak@uams.edu.
authors.forename: Grazyna
authors.initials: G
authors.lastname: Nowak
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas; and.
authors.forename: Diana
authors.initials: D
authors.lastname: Takacsova-Bakajsova
authors.affiliation: Division of Nephrology, Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Judit
authors.initials: J
authors.lastname: Megyesi
mesh_terms: D000818:Animals; D004579:Electron Transport / Q000502:physiology; D003576:Electron Transport Complex IV / Q000378:metabolism; D007511:Ischemia / Q000378:metabolism*; D007668:Kidney / Q000293:injuries / Q000503:physiopathology; D007677:Kidney Function Tests; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism*; D010101:Oxygen Consumption / Q000502:physiology; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism*
chemical_list: D003576:Electron Transport Complex IV; D051744:Protein Kinase C-epsilon
keywords: acute kidney injury; electron transport chain; hypoxia; ischemia and reperfusion; mitochondria; proteomics; renal proximal tubular cells