Erythropoietin's inhibiting impact on hepcidin expression occurs indirectly

Recalcati, Stefania; Gammella, Elena; Diaz, Victor; Noguchi, Constance Tom; Buratti, Paolo; Cairo, Gaetano; Samaja, Michele; Dey, Soumyadeep; Gassmann, Max

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.ispartofseries	American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
dc.rights	info:eu-repo/semantics/restrictedAccess
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#3.01.08
dc.relation.issn	1522-1490