TY - JOUR
T1 - Recombinant human erythropoietin-induced erythropoiesis regulates hepcidin expression over iron status in the rat
AU - Ribeiro, Sandra
AU - Garrido, Patrícia
AU - Fernandes, João
AU - Rocha, Susana
AU - Rocha-Pereira, Petronila
AU - Costa, Elísio
AU - Belo, Luís
AU - Reis, Flávio
AU - Santos-Silva, Alice
N1 - Funding Information:
This study was conducted with financial support from Portuguese Foundation for Science and Technology (FCT)/MEC through national funds and co-financed by COMPETE-FEDER ( PTDC/SAU-TOX/114253/2009 , Pest/C/SAU/3282/2013 ), by FEDER , under the Partnership Agreement PT2020 ( UID/MULTI/04378/2013 - POCI/01/0145/FERDER/007728 , UID/NEU/04539/2013 ) and by POPH/FSE ( SFRH/BD/61020/2009 , SFRH/BD/79875/2011 , SFRH/BPD/80023/2011 and SFRH/BPD/81968/2011 ). We would like to thank José Sereno, Filipa Melo and Sara Nunes for all the technical support.
Publisher Copyright:
© 2015 Elsevier Inc.
Copyright:
Copyright 2016 Elsevier B.V., All rights reserved.
PY - 2016/7/1
Y1 - 2016/7/1
N2 - The crosstalk between several factors controlling hepcidin synthesis is poorly clarified for different physiological and pathological conditions. Our aim was to study the impact of increasing recombinant human erythropoietin (rHuEPO) doses on erythropoiesis, iron metabolism and hepcidin, using a rat model. Male Wistar rats were divided in 5 groups: control (vehicle) and rHuEPO-treated groups (100, 200, 400 and 600 IU/kg body weight/week), 3 times per week, during 3 weeks. Hematological and iron data were evaluated. The expression of several genes involved in iron metabolism was analyzed by qPCR. Liver hepcidin protein was evaluated by Western Blot. The rHuEPO treatment induced erythropoiesis and increased transferrin saturation (TSAT) in a dose dependent manner. Tf receptor 2 (TfR2), hemojuvelin (HJV) and bone morphogenetic protein 6 (BMP6) were up-regulated in rHuEPO200 group. Matriptase-2 was down-regulated in rHuEPO200 group, and up-regulated in the other rHuEPO-treated groups. Hepcidin synthesis was increased in rHuEPO200 group, and repressed in the rHuEPO400 and rHuEPO600 groups. Our study showed that when a high erythropoietic stimulus occurs, hepcidin synthesis is mainly regulated by TSAT; however, when the erythropoiesis rate reaches a specific threshold, extramedullary hematopoiesis is triggered, and the control of hepcidin synthesis is switched to matriptase-2, thus inhibiting hepcidin synthesis.
AB - The crosstalk between several factors controlling hepcidin synthesis is poorly clarified for different physiological and pathological conditions. Our aim was to study the impact of increasing recombinant human erythropoietin (rHuEPO) doses on erythropoiesis, iron metabolism and hepcidin, using a rat model. Male Wistar rats were divided in 5 groups: control (vehicle) and rHuEPO-treated groups (100, 200, 400 and 600 IU/kg body weight/week), 3 times per week, during 3 weeks. Hematological and iron data were evaluated. The expression of several genes involved in iron metabolism was analyzed by qPCR. Liver hepcidin protein was evaluated by Western Blot. The rHuEPO treatment induced erythropoiesis and increased transferrin saturation (TSAT) in a dose dependent manner. Tf receptor 2 (TfR2), hemojuvelin (HJV) and bone morphogenetic protein 6 (BMP6) were up-regulated in rHuEPO200 group. Matriptase-2 was down-regulated in rHuEPO200 group, and up-regulated in the other rHuEPO-treated groups. Hepcidin synthesis was increased in rHuEPO200 group, and repressed in the rHuEPO400 and rHuEPO600 groups. Our study showed that when a high erythropoietic stimulus occurs, hepcidin synthesis is mainly regulated by TSAT; however, when the erythropoiesis rate reaches a specific threshold, extramedullary hematopoiesis is triggered, and the control of hepcidin synthesis is switched to matriptase-2, thus inhibiting hepcidin synthesis.
KW - Erythropoiesis
KW - Hepcidin
KW - Iron
KW - Matriptase-2
KW - Transferrin saturation
UR - http://www.scopus.com/inward/record.url?scp=84966393581&partnerID=8YFLogxK
U2 - 10.1016/j.bcmd.2016.04.008
DO - 10.1016/j.bcmd.2016.04.008
M3 - Article
C2 - 27282570
AN - SCOPUS:84966393581
SN - 1079-9796
VL - 59
SP - 63
EP - 70
JO - Blood Cells, Molecules, and Diseases
JF - Blood Cells, Molecules, and Diseases
ER -