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Erythropoietin's inhibiting impact on hepcidin expression occurs indirectly

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dc.contributor.author Gammella, Elena
dc.contributor.author Diaz, Victor
dc.contributor.author Recalcati, Stefania
dc.contributor.author Buratti, Paolo
dc.contributor.author Samaja, Michele
dc.contributor.author Dey, Soumyadeep
dc.contributor.author Noguchi, Constance Tom
dc.contributor.author Gassmann, Max
dc.contributor.author Cairo, Gaetano
dc.date.accessioned 2019-02-06T14:52:12Z
dc.date.available 2019-02-06T14:52:12Z
dc.date.issued 2015
dc.identifier.uri https://hdl.handle.net/20.500.12866/5266
dc.description.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 beta 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. en_US
dc.language.iso eng
dc.publisher American Physiological Society
dc.relation.ispartof urn:issn:1522-1490
dc.rights info:eu-repo/semantics/restrictedAccess
dc.rights.uri https://creativecommons.org/licenses/by-nc-nd/4.0/deed.es
dc.subject Animals en_US
dc.subject bone morphogenetic protein 6 en_US
dc.subject Cytokines/metabolism en_US
dc.subject Dose-Response Relationship, Drug en_US
dc.subject Down-Regulation en_US
dc.subject erythropoietin receptor en_US
dc.subject Erythropoietin/analogs & derivatives/pharmacology en_US
dc.subject ferroportin en_US
dc.subject Hep G2 Cells en_US
dc.subject Hepcidins/genetics/metabolism en_US
dc.subject Humans en_US
dc.subject iron en_US
dc.subject Iron/metabolism en_US
dc.subject liver en_US
dc.subject Liver/drug effects/metabolism en_US
dc.subject Male en_US
dc.subject Mice, Inbred C57BL en_US
dc.subject Mice, Inbred ICR en_US
dc.subject Mice, Knockout en_US
dc.subject Muscle Proteins/metabolism en_US
dc.subject Oligopeptides/pharmacology en_US
dc.subject Receptors, Erythropoietin/deficiency/genetics en_US
dc.subject RNA, Messenger/metabolism en_US
dc.subject Time Factors en_US
dc.title Erythropoietin's inhibiting impact on hepcidin expression occurs indirectly en_US
dc.type info:eu-repo/semantics/article
dc.identifier.doi https://doi.org/10.1152/ajpregu.00410.2014
dc.subject.ocde https://purl.org/pe-repo/ocde/ford#3.02.00 es_PE


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