期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 101, 期 26, 页码 9751-9756出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0403620101
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资金
- NIDDK NIH HHS [R37 DK016666, DK16666, R01 DK016666] Funding Source: Medline
- NIEHS NIH HHS [R01 ES008089, ES10042, R01 ES010042, ES08089, R29 ES008089] Funding Source: Medline
A basic leucine zipper transcription factor, NF-E2-related factor 2 (Nrf2), plays a critical role in the cellular defense mechanism by mediating a coordinate up-regulation of antioxidant responsive element-driven detoxification and antioxidant genes. Here, we report that targeted disruption of Nrf2 causes regenerative immune-mediated hemolytic anemia due to increased sequestration of damaged erythrocytes. Splenomegaly and spleen toxicity in Nrf2(-/-) mice raised a possibility of hemolytic anemia and splenic extramedullary hematopoiesis in Nrf2(-/-) mice. In support of this, hematology analysis revealed that Nrf2(-/-) mice suffer from anemia with abnormal red cell morphologies (i.e., Howell-Jolly bodies, acantocytes, and schistocytes). In addition, Nrf2(-/-) erythrocytes were more sensitive to H2O2-induced hemolysis, and erythrocyte-bound IgG levels were markedly increased in Nrf2(-/-) mice compared with Nrf2(+/+) mice. Because IgG bound to erythrocytes in the presence of oxidative damage in erythrocytes (regardless of Nrf2 genotype), these data support that Nrf2(-/-) erythrocytes have higher levels of damage compared with Nrf2(+/+) cells. Finally, Nrf2(-/-) mice showed increased levels of erythrocyte-bound IgG compared with Nrf2(+/+) mice after H2O2 injection in vivo, suggesting that the decreased glutathione and increased H2O2 render the Nrf2(-/-) mice more susceptible to toxicity. Taken together, these observations indicate that a chronic increase in oxidative stress due to decreased antioxidant capacity sensitizes erythrocytes and causes hemolytic anemia in Nrf2(-/-) mice, suggesting a pivotal role of Nrf2- antioxidant responsive element pathway in the cellular antioxidant defense system.
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