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Iron as the Key Modulator of Hepcidin Expression in Erythroid Antibody-Mediated Hypoplasia

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...

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Autores principales: Fernandes, J. C., Garrido, P., Ribeiro, S., Rocha-Pereira, P., Bronze-da-Rocha, E., Belo, L., Costa, E., Reis, F., Santos-Silva, A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi Publishing Corporation 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281449/
https://www.ncbi.nlm.nih.gov/pubmed/25580431
http://dx.doi.org/10.1155/2014/421304
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author Fernandes, J. C.
Garrido, P.
Ribeiro, S.
Rocha-Pereira, P.
Bronze-da-Rocha, E.
Belo, L.
Costa, E.
Reis, F.
Santos-Silva, A.
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_sort Fernandes, J. C.
collection PubMed
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.
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spelling pubmed-42814492015-01-11 Iron as the Key Modulator of Hepcidin Expression in Erythroid Antibody-Mediated Hypoplasia Fernandes, J. C. Garrido, P. Ribeiro, S. Rocha-Pereira, P. Bronze-da-Rocha, E. Belo, L. Costa, E. Reis, F. Santos-Silva, A. Biomed Res Int Research Article 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. Hindawi Publishing Corporation 2014 2014-12-18 /pmc/articles/PMC4281449/ /pubmed/25580431 http://dx.doi.org/10.1155/2014/421304 Text en Copyright © 2014 J. C. Fernandes et al. https://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Fernandes, J. C.
Garrido, P.
Ribeiro, S.
Rocha-Pereira, P.
Bronze-da-Rocha, E.
Belo, L.
Costa, E.
Reis, F.
Santos-Silva, A.
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
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_short 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
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281449/
https://www.ncbi.nlm.nih.gov/pubmed/25580431
http://dx.doi.org/10.1155/2014/421304
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