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Research ArticleToxicology

Recovery from Glycerol-Induced Acute Kidney Injury Is Accelerated by Suramin

Midhun C. Korrapati, Brooke E. Shaner and Rick G. Schnellmann
Journal of Pharmacology and Experimental Therapeutics April 2012, 341 (1) 126-136; DOI: https://doi.org/10.1124/jpet.111.190249
Midhun C. Korrapati
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Brooke E. Shaner
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Rick G. Schnellmann
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Abstract

Acute kidney injury (AKI) is a common and potentially life-threatening complication after ischemia/reperfusion and exposure to nephrotoxic agents. In this study, we examined the efficacy and mechanism(s) of suramin in promoting recovery from glycerol-induced AKI, a model of rhabdomyolysis-induced AKI. After intramuscular glycerol injection (10 ml of 50% glycerol per kilogram) into male Sprague-Dawley rats, serum creatinine maximally increased at 24 to 72 h and then decreased at 120 h. Creatinine clearance (CrCl) decreased 75% at 24 to 72 h and increased at 120 h. Suramin (1 mg/kg i.v.) administered 24 h after glycerol accelerated recovery of renal function as demonstrated by increased CrCl, decreased renal kidney injury molecule-1, and improved histopathology 72 h after glycerol injection. Suramin treatment decreased interleukin-1β (IL-1β) mRNA, transforming growth factor-β1 (TGF-β1), phospho-p65 of nuclear factor-κB (NF-κB), and cleaved caspase-3 at 48 h compared with glycerol alone. Suramin treatment also decreased glycerol-induced activation of intracellular adhesion molecule-1 (ICAM-1) and leukocyte infiltration at 72 h. Urinary/renal neutrophil gelatinase-associated lipocalin 2 (NGAL) levels, hemeoxygenase-1 expression, and renal cell proliferation were increased by suramin compared with glycerol alone at 72 h. Mechanistically, suramin decreases early glycerol-induced proinflammatory (IL-1β and NF-κB) and growth inhibitory (TGF-β1) mediators, resulting in the prevention of late downstream inflammatory effects (ICAM-1 and leukocyte infiltration) and increasing compensatory nephrogenic repair. These results support the hypothesis that delayed administration of suramin is effective in abrogating apoptosis, attenuating inflammation, and enhancing nephrogenic repair after glycerol-induced AKI.

Footnotes

  • This study was supported by National Institutes of Health National Institute of General Medical Sciences [Grant GM084147]; and the Biomedical Laboratory Research and Development Program of the Department of Veterans Affairs. Animal facilities were funded by National Institutes of Health National Center for Research Resources [Grant C06-RR015455]. This publication (or project) was also supported by the South Carolina Clinical & Translational Research Institute, with an academic home at the Medical University of South Carolina, National Institutes of Health National Center for Research Resources [Grant UL1-RR029882].

  • The contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health or the National Center for Research Resources.

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

    http://dx.doi.org/10.1124/jpet.111.190249.

  • ABBREVIATIONS:

    AKI
    acute kidney injury
    CrCl
    creatinine clearance
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    HO-1
    hemeoxygenase-1
    IL
    interleukin
    ICAM-1
    intracellular adhesion molecule-1
    I/R
    ischemia/reperfusion
    KIM-1
    kidney injury molecule-1
    MCP-1
    monocyte chemoattractant protein-1
    NF-κB
    nuclear factor κB
    NGAL
    neutrophil gelatinase-associated lipocalin 2
    OSOM
    outer stripe of the outer medulla
    PCNA
    proliferating cell nuclear antigen
    TGF-β1
    transforming growth factor-β1
    TNF-α
    tumor necrosis factor-α.

  • Received November 29, 2011.
  • Accepted January 6, 2012.
  • U.S. Government work not protected by U.S. copyright
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Journal of Pharmacology and Experimental Therapeutics: 341 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 341, Issue 1
1 Apr 2012
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Research ArticleToxicology

Suramin and Glycerol-Induced AKI

Midhun C. Korrapati, Brooke E. Shaner and Rick G. Schnellmann
Journal of Pharmacology and Experimental Therapeutics April 1, 2012, 341 (1) 126-136; DOI: https://doi.org/10.1124/jpet.111.190249

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Research ArticleToxicology

Suramin and Glycerol-Induced AKI

Midhun C. Korrapati, Brooke E. Shaner and Rick G. Schnellmann
Journal of Pharmacology and Experimental Therapeutics April 1, 2012, 341 (1) 126-136; DOI: https://doi.org/10.1124/jpet.111.190249
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