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Induction
and Nuclear Translocation of Thioredoxin by Oxidative Damage in the Mouse
Kidney: Independence of Tubular Necrosis and Sulfhydryl Depletion |
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Tomoyuki Tanaka,
Yasuyuki Nishiyama, Kunihiko Okada, Kiichi Hirota, Minoru Matsui, Junji
Yodoi, Hiroshi Hiai, and Shinya Toyokuni |
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Department
of Pathology and Biology of Diseases (TT, YN, KO, HH, ST), Graduate School
of Medicine, and Department of Biological Responses (KH, MM, JY), Institute
for Virus Research, Kyoto University, Sakyo-ku, Kyoto, Japan |
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Adult T-cell leukemia-derived
factor (ADF), originally defined as an interleukin-2 receptor inducer, is
a human thioredoxin (TRX). ADF/TRX is a conserved multifunctional reductant
presumably associated with redox regulation of the cellular environment;
it works in vitro as a cytokine, free radical scavenger, activator of transcription
factors, and substrate for several enzymes. In the present series of experiments,
we studied the expression and intracellular localization of ADF/TRX in mouse
kidney from two different renal tubular injury models: a free radical-associated
model with ferric nitrilotriacetate (Fe-NTA) and a free radical-independent
model with HgCl2. Markers of oxidative damage, such as 8-hydroxy-2`-deoxyguanosine,
thiobarbituric acid-reactive substances, and 4-hydroxy-2-nonenal-modified
proteins, were significantly increased in kidney from male C57BL/6 mice
1 hour after a single intraperitoneal injection of Fe-NTA (5 mg iron/kg).
However, in kidney from mice given a subcutaneous injection of HgCl2 (5
mg Hg/kg), none of these markers were increased, despite tubular necrosis
with sulfhydryl depletion. In the Fe-NTA model only, Northern and Western
blot analyses of the kidney revealed induction of ADF/TRX (> 2.5-fold)
after 16 hours and translocation of ADF/TRX from the cytoplasmic to nuclear
fraction (> 3.5-fold) after 24 hours. Immunohistochemistry showed a patchy
distribution of ADF/TRX in the normal renal proximal tubules. In ex vivo
experiments using serial normal kidney frozen sections, it was found that
renal proximal tubules with low expression of ADF/TRX were more vulnerable
to oxidative stress mediated by Fe-NTA. Collectively, these data suggest
that: (a) ADF/TRX is induced and translocated to nuclei by oxidative damage
mediated by Fe-NTA in the renal proximal tubules; (b) induction of ADF/TRX
is independent of tubular necrosis or sulfhydryl depletion; and (c) ADF/TRX
is involved in the cellular defense mechanisms in vivo against oxidative
damage. |
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