Iron as the key modulator of hepcidin expression in erythroid antibody-mediated hypoplasia

Detalhes bibliográficos
Autor(a) principal: Fernandes, J. C.
Data de Publicação: 2014
Outros Autores: Garrido, P., Ribeiro, S., Rocha-Pereira, P., Bronze-da-Rocha, E., Belo, L., Costa, E., Reis, F., Santos-Silva, A.
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10316/109364
https://doi.org/10.1155/2014/421304
Resumo: Erythroid hypoplasia (EH) is a rare complication associated with recombinant human erythropoietin (rHuEPO) therapies, due to development of anti-rHuEPO antibodies; however, the underlying mechanisms remain poorly clarified. Our aim was to manage a rat model of antibody-mediated EH induced by rHuEPO and study the impact on iron metabolism and erythropoiesis. Wistar rats treated during 9 weeks with a high rHuEPO dose (200 IU) developed EH, as shown by anemia, reduced erythroblasts, reticulocytopenia, and plasmatic anti-rHuEPO antibodies. Serum iron was increased and associated with mRNA overexpression of hepatic hepcidin and other iron regulatory mediators and downregulation of matriptase-2; overexpression of divalent metal transporter 1 and ferroportin was observed in duodenum and liver. Decreased EPO expression was observed in kidney and liver, while EPO receptor was overexpressed in liver. Endogenous EPO levels were normal, suggesting that anti-rHuEPO antibodies blunted EPO function. Our results suggest that anti-rHuEPO antibodies inhibit erythropoiesis causing anemia. This leads to a serum iron increase, which seems to stimulate hepcidin expression despite no evidence of inflammation, thus suggesting iron as the key modulator of hepcidin synthesis. These findings might contribute to improving new therapeutic strategies against rHuEPO resistance and/or development of antibody-mediated EH in patients under rHuEPO therapy.
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spelling Iron as the key modulator of hepcidin expression in erythroid antibody-mediated hypoplasiaAnemia, AplasticAnimalsAntibodiesErythropoiesisErythropoietinGene Expression RegulationHepcidinsHumansIronMembrane ProteinsRatsRats, WistarRecombinant ProteinsSerine EndopeptidasesErythroid hypoplasia (EH) is a rare complication associated with recombinant human erythropoietin (rHuEPO) therapies, due to development of anti-rHuEPO antibodies; however, the underlying mechanisms remain poorly clarified. Our aim was to manage a rat model of antibody-mediated EH induced by rHuEPO and study the impact on iron metabolism and erythropoiesis. Wistar rats treated during 9 weeks with a high rHuEPO dose (200 IU) developed EH, as shown by anemia, reduced erythroblasts, reticulocytopenia, and plasmatic anti-rHuEPO antibodies. Serum iron was increased and associated with mRNA overexpression of hepatic hepcidin and other iron regulatory mediators and downregulation of matriptase-2; overexpression of divalent metal transporter 1 and ferroportin was observed in duodenum and liver. Decreased EPO expression was observed in kidney and liver, while EPO receptor was overexpressed in liver. Endogenous EPO levels were normal, suggesting that anti-rHuEPO antibodies blunted EPO function. Our results suggest that anti-rHuEPO antibodies inhibit erythropoiesis causing anemia. This leads to a serum iron increase, which seems to stimulate hepcidin expression despite no evidence of inflammation, thus suggesting iron as the key modulator of hepcidin synthesis. These findings might contribute to improving new therapeutic strategies against rHuEPO resistance and/or development of antibody-mediated EH in patients under rHuEPO therapy.Hindawi2014info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://hdl.handle.net/10316/109364http://hdl.handle.net/10316/109364https://doi.org/10.1155/2014/421304eng2314-61332314-6141Fernandes, J. C.Garrido, P.Ribeiro, S.Rocha-Pereira, P.Bronze-da-Rocha, E.Belo, L.Costa, E.Reis, F.Santos-Silva, A.info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-10-11T09:49:10Zoai:estudogeral.uc.pt:10316/109364Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:25:33.927391Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Iron as the key modulator of hepcidin expression in erythroid antibody-mediated hypoplasia
title Iron as the key modulator of hepcidin expression in erythroid antibody-mediated hypoplasia
spellingShingle Iron as the key modulator of hepcidin expression in erythroid antibody-mediated hypoplasia
Fernandes, J. C.
Anemia, Aplastic
Animals
Antibodies
Erythropoiesis
Erythropoietin
Gene Expression Regulation
Hepcidins
Humans
Iron
Membrane Proteins
Rats
Rats, Wistar
Recombinant Proteins
Serine Endopeptidases
title_short Iron as the key modulator of hepcidin expression in erythroid antibody-mediated hypoplasia
title_full Iron as the key modulator of hepcidin expression in erythroid antibody-mediated hypoplasia
title_fullStr Iron as the key modulator of hepcidin expression in erythroid antibody-mediated hypoplasia
title_full_unstemmed Iron as the key modulator of hepcidin expression in erythroid antibody-mediated hypoplasia
title_sort Iron as the key modulator of hepcidin expression in erythroid antibody-mediated hypoplasia
author Fernandes, J. C.
author_facet Fernandes, J. C.
Garrido, P.
Ribeiro, S.
Rocha-Pereira, P.
Bronze-da-Rocha, E.
Belo, L.
Costa, E.
Reis, F.
Santos-Silva, A.
author_role author
author2 Garrido, P.
Ribeiro, S.
Rocha-Pereira, P.
Bronze-da-Rocha, E.
Belo, L.
Costa, E.
Reis, F.
Santos-Silva, A.
author2_role author
author
author
author
author
author
author
author
dc.contributor.author.fl_str_mv Fernandes, J. C.
Garrido, P.
Ribeiro, S.
Rocha-Pereira, P.
Bronze-da-Rocha, E.
Belo, L.
Costa, E.
Reis, F.
Santos-Silva, A.
dc.subject.por.fl_str_mv Anemia, Aplastic
Animals
Antibodies
Erythropoiesis
Erythropoietin
Gene Expression Regulation
Hepcidins
Humans
Iron
Membrane Proteins
Rats
Rats, Wistar
Recombinant Proteins
Serine Endopeptidases
topic Anemia, Aplastic
Animals
Antibodies
Erythropoiesis
Erythropoietin
Gene Expression Regulation
Hepcidins
Humans
Iron
Membrane Proteins
Rats
Rats, Wistar
Recombinant Proteins
Serine Endopeptidases
description Erythroid hypoplasia (EH) is a rare complication associated with recombinant human erythropoietin (rHuEPO) therapies, due to development of anti-rHuEPO antibodies; however, the underlying mechanisms remain poorly clarified. Our aim was to manage a rat model of antibody-mediated EH induced by rHuEPO and study the impact on iron metabolism and erythropoiesis. Wistar rats treated during 9 weeks with a high rHuEPO dose (200 IU) developed EH, as shown by anemia, reduced erythroblasts, reticulocytopenia, and plasmatic anti-rHuEPO antibodies. Serum iron was increased and associated with mRNA overexpression of hepatic hepcidin and other iron regulatory mediators and downregulation of matriptase-2; overexpression of divalent metal transporter 1 and ferroportin was observed in duodenum and liver. Decreased EPO expression was observed in kidney and liver, while EPO receptor was overexpressed in liver. Endogenous EPO levels were normal, suggesting that anti-rHuEPO antibodies blunted EPO function. Our results suggest that anti-rHuEPO antibodies inhibit erythropoiesis causing anemia. This leads to a serum iron increase, which seems to stimulate hepcidin expression despite no evidence of inflammation, thus suggesting iron as the key modulator of hepcidin synthesis. These findings might contribute to improving new therapeutic strategies against rHuEPO resistance and/or development of antibody-mediated EH in patients under rHuEPO therapy.
publishDate 2014
dc.date.none.fl_str_mv 2014
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10316/109364
http://hdl.handle.net/10316/109364
https://doi.org/10.1155/2014/421304
url http://hdl.handle.net/10316/109364
https://doi.org/10.1155/2014/421304
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv 2314-6133
2314-6141
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Hindawi
publisher.none.fl_str_mv Hindawi
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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