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Research ArticleToxicology

Role of Mitochondrial Oxidants in an In Vitro Model of Sepsis-Induced Renal Injury

Elina Pathak, Lee Ann MacMillan-Crow and Philip R. Mayeux
Journal of Pharmacology and Experimental Therapeutics January 2012, 340 (1) 192-201; DOI: https://doi.org/10.1124/jpet.111.183756
Elina Pathak
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Lee Ann MacMillan-Crow
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Philip R. Mayeux
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Abstract

Oxidative stress has been implicated to play a major role in multiorgan dysfunction during sepsis. To study the mechanism of oxidant generation in acute kidney injury (AKI) during sepsis, we developed an in vitro model of sepsis using primary cultures of mouse cortical tubular epithelial cells exposed to serum (2.5–10%) collected from mice at 4 h after induction of sepsis by cecal ligation and puncture (CLP) or Sham (no sepsis). CLP serum produced a concentration-dependent increase in nitric oxide (NO) (nitrate + nitrite) release at 6 h and cytotoxicity (lactate dehydrogenase release) at 18 h compared with Sham serum treatment. Before cytotoxicity there was a decrease in mitochondrial membrane potential, which was followed by increased superoxide and peroxynitrite levels compared with Sham serum. The role of oxidants was evaluated by using the superoxide dismutase mimetic and peroxynitrite scavenger manganese(III)tetrakis(1-methyl-4-pyridyl)porphyrin tetratosylate hydroxide (MnTmPyP). MnTmPyP (10–100 μM) produced a concentration-dependent preservation of ATP and protection against cytotoxicity. MnTmPyP blocked mitochondrial superoxide and peroxynitrite generation produced by CLP serum but had no effect on NO levels. Although MnTmPyP did not block the initial CLP serum-induced fall in mitochondrial membrane potential, it allowed mitochondrial membrane potential to recover. Data from this in vitro model suggest a time-dependent generation of mitochondrial oxidants, mitochondrial dysfunction, and renal tubular epithelial cell injury and support the therapeutic potential of manganese porphyrin compounds in preventing sepsis-induced AKI.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK075991] and the University of Arkansas for Medical Sciences Translational Research Institute, which is supported by the National Institutes of Health National Center for Research Resources [Grant UL1-RR029884].

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.111.183756.

  • ABBREVIATIONS:

    AKI
    acute kidney injury
    CLP
    cecal ligation and puncture
    RNS
    reactive nitrogen species
    ROS
    reactive oxygen species
    MnTmPyP
    Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin tetratosylate hydroxide
    DHR
    2-(3,6-diamino-9H-xanthen-9-yl)-benzoic acid methyl ester
    PmCTE
    primary murine cortical tubular epithelial cells
    l-NMMA
    l-NG-monomethyl arginine citrate
    1400W
    N-[[3-(aminomethyl)phenyl]methyl]-ethanimidamide dihydrochloride
    DPI
    diphenyleneiodonium chloride
    JC-1
    5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolylcarbocyanineiodide
    DAR-4M AM
    3′,6′-Bis(dimethylamino)-9-[2-acetomethoxycarbonyl-3-amino-4-(N-methylamino)phenyl]xanthylium iodide
    LDH
    lactate dehydrogenase
    NO
    nitric oxide
    NOS
    NO synthase
    iNOS
    inducible NOS
    ONOO−
    oxidant peroxynitrite
    ANOVA
    analysis of variance
    DMEM
    Dulbecco's modified Eagle's medium
    PBS
    phosphate-buffered saline
    SOD
    superoxide dismutase.

  • Received May 9, 2011.
  • Accepted October 18, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 340 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 340, Issue 1
1 Jan 2012
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Research ArticleToxicology

Mitochondrial Oxidants in an In Vitro Model of Sepsis

Elina Pathak, Lee Ann MacMillan-Crow and Philip R. Mayeux
Journal of Pharmacology and Experimental Therapeutics January 1, 2012, 340 (1) 192-201; DOI: https://doi.org/10.1124/jpet.111.183756

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Research ArticleToxicology

Mitochondrial Oxidants in an In Vitro Model of Sepsis

Elina Pathak, Lee Ann MacMillan-Crow and Philip R. Mayeux
Journal of Pharmacology and Experimental Therapeutics January 1, 2012, 340 (1) 192-201; DOI: https://doi.org/10.1124/jpet.111.183756
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