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Erythropoietin's inhibiting impact on hepcidin expression occurs indirectly.
Journal article

Erythropoietin's inhibiting impact on hepcidin expression occurs indirectly.

  • Gammella E Department of Biomedical Sciences for Health, University of Milano, Milan, Italy;
  • Diaz V Institute of Veterinary Physiology, Vetsuisse Faculty, and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland;
  • Recalcati S Department of Biomedical Sciences for Health, University of Milano, Milan, Italy;
  • Buratti P Department of Biomedical Sciences for Health, University of Milano, Milan, Italy;
  • Samaja M Department of Health Science, University of Milano, Milan, Italy;
  • Dey S Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; and.
  • Noguchi CT Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; and.
  • Gassmann M Institute of Veterinary Physiology, Vetsuisse Faculty, and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland; Universidad Peruana Cayetano Heredia, Lima, Peru.
  • Cairo G Department of Biomedical Sciences for Health, University of Milano, Milan, Italy; gaetano.cairo@unimi.it.
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  • 2014-12-19
Published in:
  • American journal of physiology. Regulatory, integrative and comparative physiology. - 2015
bone morphogenetic protein 6
erythropoietin receptor
ferroportin
iron
liver
Animals
Cytokines
Dose-Response Relationship, Drug
Down-Regulation
Erythropoietin
Hep G2 Cells
Hepcidins
Humans
Iron
Liver
Male
Mice, Inbred C57BL
Mice, Inbred ICR
Mice, Knockout
Muscle Proteins
Oligopeptides
RNA, Messenger
Receptors, Erythropoietin
Time Factors
English Under conditions of accelerated erythropoiesis, elevated erythropoietin (Epo) levels are associated with inhibition of hepcidin synthesis, a response that ultimately increases iron availability to meet the enhanced iron needs of erythropoietic cells. In the search for erythroid regulators of hepcidin, many candidates have been proposed, including Epo itself. We aimed to test whether direct interaction between Epo and the liver is required to regulate hepcidin. We found that prolonged administration of high doses of Epo in mice leads to great inhibition of liver hepcidin mRNA levels, and concomitant induction of the hepcidin inhibitor erythroferrone (ERFE). Epo treatment also resulted in liver iron mobilization, mediated by increased ferroportin activity and accompanied by reduced ferritin levels and increased TfR1 expression. The same inhibitory effect was observed in mice that do not express the homodimeric Epo receptor (EpoR) in liver cells because EpoR expression is restricted to erythroid cells. Similarly, liver signaling pathways involved in hepcidin regulation were not influenced by the presence or absence of hepatic EpoR. Moreover, Epo analogs, possibly interacting with the postulated heterodimeric β common EpoR, did not affect hepcidin expression. These findings were supported by the lack of inhibition on hepcidin found in hepatoma cells exposed to various concentrations of Epo for different periods of times. Our results demonstrate that hepcidin suppression does not require the direct binding of Epo to its liver receptors and rather suggest that the role of Epo is to stimulate the synthesis of the erythroid regulator ERFE in erythroblasts, which ultimately downregulates hepcidin.
Language
  • English
Open access status
green
Identifiers
Persistent URL
https://sonar.ch/global/documents/103169
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