Deletion of protein kinase C-ε attenuates mitochondrial dysfunction and ameliorates ischemic renal injury

Am J Physiol Renal Physiol. 2017 Jan 1;312(1):F109-F120. doi: 10.1152/ajprenal.00115.2016. Epub 2016 Oct 19.

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.

Keywords: acute kidney injury; electron transport chain; hypoxia; ischemia and reperfusion; mitochondria; proteomics; renal proximal tubular cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Electron Transport / physiology
  • Electron Transport Complex IV / metabolism
  • Ischemia / metabolism*
  • Kidney / injuries
  • Kidney / physiopathology
  • Kidney Function Tests
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Mitochondrial Membranes / metabolism*
  • Oxygen Consumption / physiology
  • Protein Kinase C-epsilon / genetics
  • Protein Kinase C-epsilon / metabolism*

Substances

  • Electron Transport Complex IV
  • Protein Kinase C-epsilon