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Article: Targeted disruption of Nrf2 causes regenerative immune-mediated hemolytic anemia

TitleTargeted disruption of Nrf2 causes regenerative immune-mediated hemolytic anemia
Authors
Issue Date2004
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
Citation
Proceedings Of The National Academy Of Sciences Of The United States Of America, 2004, v. 101 n. 26, p. 9751-9756 How to Cite?
AbstractA 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.
Persistent Identifierhttp://hdl.handle.net/10722/49047
ISSN
2015 Impact Factor: 9.423
2015 SCImago Journal Rankings: 6.883
PubMed Central ID
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorLee, JMen_HK
dc.contributor.authorChan, Ken_HK
dc.contributor.authorKan, YWen_HK
dc.contributor.authorJohnson, JAen_HK
dc.date.accessioned2008-06-12T06:33:16Z-
dc.date.available2008-06-12T06:33:16Z-
dc.date.issued2004en_HK
dc.identifier.citationProceedings Of The National Academy Of Sciences Of The United States Of America, 2004, v. 101 n. 26, p. 9751-9756en_HK
dc.identifier.issn0027-8424en_HK
dc.identifier.urihttp://hdl.handle.net/10722/49047-
dc.description.abstractA 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.en_HK
dc.format.extent386 bytes-
dc.format.mimetypetext/html-
dc.languageengen_HK
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.orgen_HK
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of Americaen_HK
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.rightsNational Academy of Sciences Proceedings. Copyright © National Academy of Sciences.en_HK
dc.subject.meshAnemia, Hemolytic, Autoimmune - genetics - immunology - metabolism - pathologyen_HK
dc.subject.meshDNA-Binding Proteins - deficiency - genetics - metabolismen_HK
dc.subject.meshGene Deletionen_HK
dc.subject.meshTrans-Activators - deficiency - genetics - metabolismen_HK
dc.subject.meshAntioxidants - metabolismen_HK
dc.titleTargeted disruption of Nrf2 causes regenerative immune-mediated hemolytic anemiaen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0027-8424&volume=101&issue=26&spage=9751&epage=9756&date=2004&atitle=Targeted+disruption+of+Nrf2+causes+regenerative+immune-mediated+hemolytic+anemiaen_HK
dc.identifier.emailChan, K: kaimin@hkucc.hku.hken_HK
dc.identifier.authorityChan, K=rp00489en_HK
dc.description.naturepublished_or_final_versionen_HK
dc.identifier.doi10.1073/pnas.0403620101en_HK
dc.identifier.pmid15210949-
dc.identifier.pmcidPMC470746en_HK
dc.identifier.scopuseid_2-s2.0-3042716482en_HK
dc.identifier.hkuros113814-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-3042716482&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume101en_HK
dc.identifier.issue26en_HK
dc.identifier.spage9751en_HK
dc.identifier.epage9756en_HK
dc.identifier.isiWOS:000222405600043-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridLee, JM=25622544900en_HK
dc.identifier.scopusauthoridChan, K=7406032228en_HK
dc.identifier.scopusauthoridKan, YW=7102524964en_HK
dc.identifier.scopusauthoridJohnson, JA=7406813149en_HK
dc.identifier.citeulike6414047-

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