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Erythropoietin's inhibiting impact on hepcidin expression occurs indirectly


Gammella, Elena; Diaz, Victor; Recalcati, Stefania; Buratti, Paolo; Samaja, Michele; Dey, Soumyadeep; Noguchi, Constance Tom; Gassmann, Max; Cairo, Gaetano (2015). Erythropoietin's inhibiting impact on hepcidin expression occurs indirectly. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 308(4):R330-5.

Abstract

Under conditions of accelerated erythropoiesis, elevated erythropoietin (Epo) levels are associated to 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 analogues 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, that ultimately downregulates hepcidin.

Abstract

Under conditions of accelerated erythropoiesis, elevated erythropoietin (Epo) levels are associated to 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 analogues 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, that ultimately downregulates hepcidin.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Center for Integrative Human Physiology
05 Vetsuisse Faculty > Institute of Veterinary Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:15 February 2015
Deposited On:23 Jan 2015 06:45
Last Modified:05 Apr 2016 18:45
Publisher:American Physiological Society
ISSN:0363-6119
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1152/ajpregu.00410.2014
PubMed ID:25519735

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