Toxicologic Pathology

 

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0192623307311401v1
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First published on March 25, 2008, doi:10.1177/0192623307311401

Toxicologic Pathology 2008;36:353.

A more recent version of this article appeared on February 1, 2008

Article

A Possible Role of Nrf2 in Prevention of Renal Oxidative Damage by Ferric Nitrilotriacetate

Keita Kanki, Takashi Umemura*, Yasuki Kitamura, Yuji Ishii, Yuichi Kuroiwa, Yukio Kodama, Ken Itoh, Masayuki Yamamoto, Akiyoshi Nishikawa, and Masao Hirose

* To whom correspondence should be addressed. E-mail: umemura{at}nihs.go.jp.


  Abstract
To ascertain the possible roles of nuclear erythroid 2 p45-related factor 2 (Nrf2), a key transcription factor of phase 2 drug-metabolizing enzymes, in renal cellular defense against oxidative stress, wild-type and Nrf2-knockout (–/–) mice were treated with ferric nitrilotriacetate (Fe-NTA) at doses of 3 or 6 mg iron/kg body weight. After Fe-NTA treatment, Nrf2 (–/–) mice consistently showed lower levels of glutathione (GSH) in the kidney at the low dose and the liver at the high dose than the wild-type mice. Gamma-glutamylcysteine ligase (GCL) activity in the kidney and liver of Nrf2 (–/–) mice was also consistently lower than in wild-type mice after the Fe-NTA treatment. Histopathological examination revealed that nephrotoxicity of Fe-NTA, reflected in necrosis of renal tubule epithelial cells following nuclear damage, was more severe in the Nrf2 (–/–) mice than in their wild-type counterparts. Overall, the data suggest that Nrf2 (–/–) mice are unable to compensate for depletion of renal GSH because of oxidative stress, being more susceptible to Fe-NTA-induced nephrotoxicity. In conclusion, the present study showed that Nrf2 might play an important role in protecting cells from oxidative stress in the kidney through its regulation of antioxidant enzymes.


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