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Research ArticleArticle

Spin Trap (N-t-butyl-α-phenylnitrone)-Mediated Suprainduction of Heme Oxygenase-1 in Kidney Ischemia/Reperfusion Model: Role of the Oxygenase in Protection against Oxidative Injury

Mahin D. Maines, Vulapali S. Raju and Nariman Panahian
Journal of Pharmacology and Experimental Therapeutics November 1999, 291 (2) 911-919;
Mahin D. Maines
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Vulapali S. Raju
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Nariman Panahian
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Abstract

In mammals the rate-limiting step in heme catabolism is the heme oxygenase (HO) system. Two isozymes, HO-1 and HO-2, oxidatively cleave the substrate to form biliverdin, and the potential cellular messenger, CO; the chelated iron is released as the result of the tetrapyrrole ring opening. Biliverdin is subsequently reduced to bilirubin, an antioxidant, by biliverdin reductase. The aim of the present study was to investigate the involvement of HO-1, a heat shock/stress protein, in protection offered by the spin trap agent,N-tert-butyl-α-phenyl-nitrone (PBN), against kidney ischemia/reperfusion injury. For this, HO-1 expression and assessment of the parameters associated with tissue-oxidative injury were compared in the presence or absence of PBN pretreatment of rats (100 mg/kg i.p., 30 min) before the onset of 30-min ischemia. Twenty-four hours after reperfusion, Northern blot analysis showed an unprecedented ∼37-fold increase in 1.8-kb HO-1 mRNA in PBN pretreated rat kidney; HO-2 mRNA levels did not increase. At 48 h, the levels of HO-1 mRNA remained nearly 14-fold higher than the control value. In the absence of PBN, the levels measured approximately 5- and 2-fold higher than control values at the 24- and 48-h intervals, respectively. PBN pretreatment also resulted in a most impressive increase in the levels of HO-1 protein as judged by Western blot analysis and measurement of enzyme activity at the 24-h time point. As detected by immunohistochemical analysis, PBN pretreatment caused an increase in HO-1 and biliverdin reductase-immunoreactive proteins in the cortex and in the outer stripe of the outer medulla. In the absence of PBN pretreatment, there was an intense immunostaining for HO-1 in the medullary rays, which corresponded with iron and lipid peroxidation staining of the region; these observations were not made with PBN-pretreated kidneys. Collectively, the findings are consistent with the likelihood that suprainduction of HO-1 gene expression protects the kidney from free radical-mediated injury by increasing the capacity to produce the potent cellular antioxidant bilirubin. We also suggest spin trap-mediated protection against ischemia/reperfusion injury is likely due to a sustained elevation of HO-1 gene expression by formation of stable radicals.

Footnotes

  • Send reprint requests to: Mahin D. Maines, Ph.D., Department of Biochemistry and Biophysics, University of Rochester Medical Center, 601 Elmwood Ave., Rochester, NY 14642-0001. E-mail:MAHIN_MAINES{at}URMC.ROCHESTER.EDU

  • ↵1 This study was supported by National Institute for Environmental Health Sciences Grant ES04066.

  • ↵2 Current address: Department of Medicine, Cardiology Unit, University of Rochester Medical Center, 601 Elmwood Ave., Rochester, NY 14642-0001.

  • Abbreviations:
    HO
    heme oxygenase
    HSP
    heat shock/stress protein
    PBN
    N-tert-butyl-α-phenyl nitrone
    DMSO
    dimethyl sulfoxide
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    TBS
    Tris-buffered saline
    DAB
    diaminobenzidine
    • Received April 29, 1999.
    • Accepted July 26, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 291 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 291, Issue 2
1 Nov 1999
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Research ArticleArticle

Spin Trap (N-t-butyl-α-phenylnitrone)-Mediated Suprainduction of Heme Oxygenase-1 in Kidney Ischemia/Reperfusion Model: Role of the Oxygenase in Protection against Oxidative Injury

Mahin D. Maines, Vulapali S. Raju and Nariman Panahian
Journal of Pharmacology and Experimental Therapeutics November 1, 1999, 291 (2) 911-919;

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Research ArticleArticle

Spin Trap (N-t-butyl-α-phenylnitrone)-Mediated Suprainduction of Heme Oxygenase-1 in Kidney Ischemia/Reperfusion Model: Role of the Oxygenase in Protection against Oxidative Injury

Mahin D. Maines, Vulapali S. Raju and Nariman Panahian
Journal of Pharmacology and Experimental Therapeutics November 1, 1999, 291 (2) 911-919;
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