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

¹ Division of Pathology and
² Division of Toxicology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan;
³ Center for Advanced Medical Research, School of Medicine, Hirosaki University, 5 Zaihu-cho, Hirosaki-shi, Aomori, Japan and
⁴ Institute of Basic Medical Sciences and Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tennoudai, Tsukuba 305, Ibaraki, Japan

Correspondence: Address correspondence to: Takashi Umemura, Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan; e-mail: umemura{at}nihs.go.jp.

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.

Key Words: Fe-NTA • Nrf2 • kidney • oxidative stress

Abbreviations: ARE, antioxidant-response element • Fe-NTA, ferric nitrilotri-acetate • GCL, gamma-glutamylcysteine ligase • GSH, glutathione • GSS, glutathione synthetase • H&E, hematoxylin and eosin • Keap1, Kelch-like ECH-associated protein 1 • NDA, 2 3-naphthalenedicarboxyaldehyde • MDA, malondialdehyde • Nrf2, nuclear erythroid 2 p45-related factor 2 • ROS, reactive oxygen species • TBARS, thiobarbituric acid-reactive substances • PCR, polymerase chain reaction

This version was published on February 1, 2008

Toxicologic Pathology, Vol. 36, No. 2, 353-361 (2008)
DOI: 10.1177/0192623307311401


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