title: Erythropoietin stimulation decreases hepcidin expression through hematopoietic activity on bone marrow cells in mice.
abstract: Erythropoiesis-stimulating agents (ESA) are now central to the treatment of renal anemia and are associated with improved clinical outcomes. It is well known that erythropoietin (EPO) is a key regulator of erythropoiesis through its promotion of red blood cell production. In order to investigate the role of ESA on iron metabolism, we analyzed the regulation of the iron regulatory hormone hepcidin by ESA treatment in a bone marrow transplant model in mouse. After treating C57BL/6 mice with continuous erythropoietin receptor activator (C.E.R.A.), recombinant human epoetin-β (rhEPO), or recombinant human carbamylated epoetin-β (rhCEPO), we investigated serum hepcidin concentrations and parameters of erythropoiesis. Serum hepcidin concentrations after rhEPO treatment were analyzed in mice subjected to total body irradiation followed by bone marrow transplantation. C.E.R.A. administration caused long-term downregulation of serum hepcidin levels. Serum hepcidin levels in rhEPO-treated mice decreased significantly, whereas there was no change in rhCEPO-treated mice. The reduction in circulating hepcidin levels after rhEPO administration was not observed in irradiated mice. Finally, bone marrow transplantation recovered the response to rhEPO administration that downregulates hepcidin concentration in irradiated mice. These results indicate that ESA treatment downregulates serum hepcidin concentrations, mainly by indirect mechanisms affecting hematopoietic activity in bone marrow cells.
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa, 247-8530, Japan. sasaki.yusuke@chugai-pharm.co.jp
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Mariko
authors.initials: M
authors.lastname: Noguchi-Sasaki
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yasuno
authors.forename: Keigo
authors.initials: K
authors.lastname: Yorozu
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Shimonaka
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis* / Q000235:genetics; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000378:metabolism; D016026:Bone Marrow Transplantation; D003114:Colony-Forming Units Assay; D015536:Down-Regulation; D004920:Erythropoiesis / Q000187:drug effects* / Q000235:genetics; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D064451:Hepcidins; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000096:biosynthesis; D011828:Radiation Chimera; D011833:Radiation Injuries, Experimental / Q000378:metabolism / Q000601:surgery; D060888:Real-Time Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000494:pharmacology; D013047:Specific Pathogen-Free Organisms; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D023181:Antimicrobial Cationic Peptides; C578702:HAMP protein, human; C579599:Hamp protein, mouse; D064451:Hepcidins; D012333:RNA, Messenger; D011994:Recombinant Proteins; C488171:carbamylated erythropoietin; C103998:epoetin beta; D004921:Erythropoietin