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Cited by 120Genomics, phytochemicals, and oxidative stressBlood groups and transfusionHemoglobinopathies and Related Disorders

Targeted disruption of Nrf2 causes regenerative immune-mediated hemolytic anemia

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Lee, Jong-Min, Chan, Kaimin, Kan, Yuet Wai, Johnson, Jeffrey A.·2004·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0403620101PMC PMC470746
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Abstract

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 H(2)O(2)-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 H(2)O(2) injection in vivo, suggesting that the decreased glutathione and increased H(2)O(2) 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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  • The HIF and NRF2 pathways are related with anemia.

    “Furthermore, the hypoxia inducible factor (HIF) and the nuclear factor-erythroid 2-related factor 2 (NRF2) pathways are related with anemia (Lee et al., 2004;Silva and Faustino, 2015).”

    From Identification of Candidate Signature Genes and Key Regulators Associated With Trypanotolerance in the Sheko Breed (2019) · cites this paper as Lee et al., 2004

    The Results and Conclusion report that Nrf2-deficient mice develop hemolytic anemia, supporting the NRF2 portion of the jointly cited sentence. Our copy does not address a relationship between the HIF pathway and anemia, so it does not support that portion of the sentence. (LLM, conf=0.84)

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Cited by

Sorted by citations

Authors
Lee, J.-M., Chan, K., Kan, Y. W., & Johnson, J. A.
Affiliations
  • School of Pharmacy, Molecular and Environmental Toxicology Center, Waisman Center, and Center for Neuroscience, University of Wisconsin, Madison, WI 53705; Department of Medicine, University of Hong Kong, Pokfulam Road, Hong Kong; and Cardiovascular Research Institute, Howard Hughes Medical Institute, and Department of Laboratory Medicine, University of California, San Francisco, CA 94143
  • Howard Hughes Medical Institute (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2004-06-21
Volume
101
Issue
26
Pages
9751-9756
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0403620101
PMC
PMC470746
OpenAlex
W1967411041
Cited by
120
References
1
Citations by year
2025: 2 · 2024: 6 · 2023: 7 · 2022: 2 · 2021: 7 · 2020: 5 · 2019: 13 · 2018: 2 · 2017: 2 · 2016: 5 · 2015: 7 · 2014: 4 · 2013: 9 · 2012: 8
FWCI
2.25
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
Funders
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK16666, R01DK016666, R37DK016666)
  • National Institute of Environmental Health Sciences (ES10042, R01ES010042, ES08089, R01ES008089, R29ES008089)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
  • Health Sciences › Medicine › Hematology › Blood groups and transfusion
  • Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
Keywords
Nrf2, immune-mediated hemolytic anemia, erythrocyte damage, oxidative stress, antioxidant defense, splenomegaly, extramedullary hematopoiesis, erythrocyte morphology, hydrogen peroxide-induced hemolysis, glutathione, Nrf2 knockout mice
MeSH terms
Anemia, Hemolytic, Autoimmune, Animals, Antioxidants, DNA-Binding Proteins, Erythrocytes, Gene Expression Regulation, Genotype, Hemolysis, Hydrogen Peroxide, Immunoglobulin G, Phenotype, Spleen, Splenomegaly, Tooth, Trans-Activators, Gene Deletion, Mice, Knockout, Oxidative Stress, Response Elements, Cell Size, NF-E2-Related Factor 2, Mice

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