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PMID: 15210949 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Targeted disruption of Nrf2 causes regenerative immune-mediated hemolytic anemia.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 101 ·No. 26 ·2004-06-29 ·Pages 9751-6

Lee JM, Chan K, Kan YW, Johnson JA

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.

MeSH Terms
Anemia, Hemolytic, Autoimmune/genetics,immunology,metabolism,pathology Animals Antioxidants/metabolism Cell Size/drug effects DNA-Binding Proteins/deficiency,genetics,metabolism Erythrocytes/drug effects,immunology,metabolism,pathology Gene Deletion Gene Expression Regulation Genotype Hemolysis/drug effects Hydrogen Peroxide/pharmacology Immunoglobulin G/immunology Mice Mice, Knockout NF-E2-Related Factor 2 Oxidative Stress/drug effects Phenotype Response Elements/genetics Spleen/metabolism,pathology Splenomegaly/genetics,pathology Tooth/physiology Trans-Activators/deficiency,genetics,metabolism
Chemicals
Antioxidants DNA-Binding Proteins Immunoglobulin G NF-E2-Related Factor 2 Nfe2l2 protein, mouse Trans-Activators Hydrogen Peroxide
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Lee Jong-Min
School of Pharmacy, Molecular and Environmental Toxicology Center, University of Wisconsin, Madison, WI 53705, USA.
Chan Kaimin
Kan Yuet Wai
Johnson Jeffrey A
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0403620101
Published
2004-06-29
Epub
2004-00-21
Pages
9751-6
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC470746
Subset
IM
Grants
NIDDK NIH HHS · R37 DK016666 · United States
NIDDK NIH HHS · DK16666 · United States
NIEHS NIH HHS · R01 ES008089 · United States
NIDDK NIH HHS · R01 DK016666 · United States
NIEHS NIH HHS · R29 ES008089 · United States
NIEHS NIH HHS · R01 ES010042 · United States
NIEHS NIH HHS · ES10042 · United States
NIEHS NIH HHS · ES08089 · United States
External Links
PubMed source DOI: 10.1073/pnas.0403620101 PMC Full Text View journal details
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