title: Liver iron is a major regulator of hepcidin gene expression via BMP/SMAD pathway in a rat model of chronic renal failure under treatment with high rHuEPO doses.
abstract: Hepcidin is the major central regulator of iron metabolism, controlling iron absorption and mobilization. Considering its interaction with several factors that are altered in chronic kidney disease (CKD), particularly in hyporesponsive CKD patients under therapy with high recombinant human erythropoietin (rHuEPO) doses, it was aimed to study the impact of increasing rHuEPO doses on the regulation of iron-hepcidin metabolism. The blood, cellular, and tissue studies, using the remnant kidney rat model of CKD induced by 5/6 nephrectomy, under rHuEPO (100, 200, 400, and 600 IU/Kg body weight [BW]/week) treatment during 3 weeks were performed. It was found that the rHuEPO stimulus triggered a first wave to achieve correction of anemia, by inhibiting hepcidin synthesis, favoring erythropoiesis and iron absorption; this continuous stimulus enhanced iron absorption leading to iron overload, as showed by the hepatic iron deposits found in rats treated with higher rHuEPO dose that seems to trigger the upregulation of hepcidin synthesis through the activation of the BMP6/SMAD pathway. The data suggested that liver iron overload was an important stimuli for hepcidin synthesis, stronger than the inhibitory effect of high rHuEPO doses; moreover, the findings raised the hypothesis that when high inflammation (triggering hepcidin expression) was associated with increased iron stores in hemodialysis patients, hepcidin expression was also upregulated via BMP6, enhancing hepcidin synthesis, leading, therefore, to worsening of anemia and, eventually, to a hyporesponse/resistance to rHuEPO therapy. © 2016 BioFactors, 42(3):296-306, 2016.
authors.affiliation: Research Unit on Applied Molecular Biosciences (UCIBIO), REQUIMTE, Department of Biological Sciences, Laboratory of Biochemistry, Faculty of Pharmacy, University of Porto, Porto, Portugal.
authors.forename: Sandra
authors.initials: S
authors.lastname: Ribeiro
authors.affiliation: Laboratory of Pharmacology & Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Garrido
authors.affiliation: Laboratory of Pharmacology & Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.|Center for Neuroscience and Cell Biology-Institute for Biomedical Imaging and Life Sciences (CNC.IBILI) Research Unit, University of Coimbra, Coimbra, Portugal.
authors.forename: João
authors.initials: J
authors.lastname: Fernandes
authors.affiliation: Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal.
authors.forename: Petronila
authors.initials: P
authors.lastname: Rocha-Pereira
authors.affiliation: Research Unit on Applied Molecular Biosciences (UCIBIO), REQUIMTE, Department of Biological Sciences, Laboratory of Biochemistry, Faculty of Pharmacy, University of Porto, Porto, Portugal.
authors.forename: Elísio
authors.initials: E
authors.lastname: Costa
authors.affiliation: Research Unit on Applied Molecular Biosciences (UCIBIO), REQUIMTE, Department of Biological Sciences, Laboratory of Biochemistry, Faculty of Pharmacy, University of Porto, Porto, Portugal.
authors.forename: Luís
authors.initials: L
authors.lastname: Belo
authors.affiliation: Laboratory of Pharmacology & Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.|Center for Neuroscience and Cell Biology-Institute for Biomedical Imaging and Life Sciences (CNC.IBILI) Research Unit, University of Coimbra, Coimbra, Portugal.
authors.forename: Flávio
authors.initials: F
authors.lastname: Reis
authors.affiliation: Research Unit on Applied Molecular Biosciences (UCIBIO), REQUIMTE, Department of Biological Sciences, Laboratory of Biochemistry, Faculty of Pharmacy, University of Porto, Porto, Portugal.
authors.forename: Alice
authors.initials: A
authors.lastname: Santos-Silva
mesh_terms: D000740:Anemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D055418:Bone Morphogenetic Protein 6 / Q000235:genetics; D004921:Erythropoietin / Q000008:administration & dosage / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D064451:Hepcidins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007676:Kidney Failure, Chronic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000235:genetics
chemical_list: C525818:Bmp6 protein, rat; D055418:Bone Morphogenetic Protein 6; D064451:Hepcidins; D011994:Recombinant Proteins; D051785:Smad Proteins; D004921:Erythropoietin; D007501:Iron
keywords: BMP6; chronic renal failure; erythropoietin; hepcidin; iron overload