Cited by 59Iron Metabolism and DisordersErythropoietin and Anemia TreatmentHemoglobin structure and function

Erythropoietin's inhibiting impact on hepcidin expression occurs indirectly

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Gammella, Elena, Diaz, Victor, Recalcati, Stefania, Buratti, Paolo, Samaja, Michele, Dey, Soumyadeep, Noguchi, Constance Tom, Gassmann, Max +1 more·2015·American Journal of Physiology-Regulatory, Integrative and Comparative Physiology

Abstract

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.

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Authors
Gammella, E., Diaz, V., Recalcati, S., Buratti, P., Samaja, M., Dey, S., Noguchi, C. T., Gassmann, M., & Cairo, G.
Affiliations
  • University of Milan (IT)
  • Institute of Veterinary Physiology, Vetsuisse Faculty, and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland;
  • National Institutes of Health (US)
  • Universidad Peruana Cayetano Heredia (PE)
Corresponding author
Cairo, Gaetano
Venue
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
Published
2015-02-15
Volume
308
Issue
4
Pages
R330-R335
ISSN
  • 0363-6119 (ISSN-L)
  • 1522-1490
OpenAlex
W2112234535
Cited by
59
References
25
Citations by year
2025: 2 · 2024: 3 · 2023: 6 · 2022: 6 · 2021: 6 · 2020: 2 · 2019: 7 · 2018: 7 · 2017: 6 · 2016: 8 · 2015: 6
FWCI
4.73
Type
journal article
Language
en
Open access
Locations
  • American Journal of Physiology-Regulatory, Integrative and Comparative Physiology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
  • Zurich Open Repository and Archive (University of Zurich)
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
Keywords
erythropoietin, hepcidin, erythroferrone, erythropoietin receptor, ferroportin, ferritin, transferrin receptor 1, iron homeostasis, erythropoiesis, erythroid cells, hepatoma cells
MeSH terms
Animals, Dose-Response Relationship, Drug, Erythropoietin, Humans, Iron, Liver, Male, Mice, Inbred C57BL, Mice, Inbred ICR, Muscle Proteins, Oligopeptides, RNA, Messenger, Time Factors, Down-Regulation, Cytokines, Receptors, Erythropoietin, Mice, Knockout, Hep G2 Cells, Hepcidins

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