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Vol. 291, Issue 2, 911-919, November 1999
-phenylnitrone)-Mediated
Suprainduction of Heme Oxygenase-1 in Kidney Ischemia/Reperfusion
Model: Role of the Oxygenase in Protection against Oxidative
Injury1
Department of Biochemistry and Biophysics, University of Rochester
Medical Center, Rochester, New York
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-
-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.
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