title: Circulating factors are involved in hypoxia-induced hepcidin suppression.
abstract: Hepcidin transcription is strongly down-regulated under hypoxic conditions, however whether hypoxia inhibits hepcidin directly or indirectly is still unknown. We investigated the time course of hypoxia-mediated hepcidin down-regulation in vivo in healthy volunteers exposed to hypobaric hypoxia at high altitude and, based on the hypothesis that circulating factors are implicated in hepcidin inhibition, we analyzed the effect of sera of these volunteers exposed to normoxia and hypoxia on hepcidin expression in Huh-7 cell lines. Hypoxia led to a significant hepcidin down-regulation in vivo that was almost complete within 72h of exposure and followed erythropoietin induction. This delay in hepcidin down-regulation suggests the existence of soluble factor/s regulating hepcidin production. We then stimulated HuH-7 cells with normoxic and hypoxic sera to analyze the effects of sera on hepcidin regulation. Hypoxic sera had a significant inhibitory effect on hepcidin promoter activity assessed by a luciferase assay, although the amount of such decrease was not as relevant as that observed in vivo. Cellular mRNA analysis showed that a number of volunteers' sera inhibited hepcidin expression, concurrently with ID1 inhibition, suggesting that inhibitory factor(s) may act through the SMAD-pathway.
authors: Department of Health Science, University Milano-Bicocca, Monza, Italy.
authors: Giulia
authors: G
authors: Ravasi
authors: Department of Health Science, University Milano-Bicocca, Monza, Italy.
authors: Sara
authors: S
authors: Pelucchi
authors: Department of Health Science, University Milano-Bicocca, Monza, Italy.
authors: Federico
authors: F
authors: Greni
authors: San Gerardo Hospital, Monza, Italy.
authors: Raffaella
authors: R
authors: Mariani
authors: Department of Health Science, University Milano-Bicocca, Monza, Italy; Department of Cardiology, Italian Institute for Auxology, Milan, Italy.
authors: Andrea
authors: A
authors: Giuliano
authors: Department of Health Science, University Milano-Bicocca, Monza, Italy; San Gerardo Hospital, Monza, Italy; Department of Cardiology, Italian Institute for Auxology, Milan, Italy.
authors: Gianfranco
authors: G
authors: Parati
authors: Division of Genetics and Cell Biology, San Raffaele Scientific Institute and Vita Salute University, Milan, Italy.
authors: Laura
authors: L
authors: Silvestri
authors: Department of Health Science, University Milano-Bicocca, Monza, Italy; San Gerardo Hospital, Monza, Italy; Consortium of Human Molecular Genetics, Monza, Italy. Electronic address: alberto.piperno@unimib.it.
authors: Alberto
authors: A
authors: Piperno
mesh_terms: D000328:Adult; D000531:Altitude; D001685:Biological Factors / Q000097:blood / Q000494:pharmacology*; D002460:Cell Line; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D064451:Hepcidins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000097:blood*; D051798:Inhibitor of Differentiation Protein 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D001685:Biological Factors; C554270:EPO protein, human; C578702:HAMP protein, human; D064451:Hepcidins; C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; D012333:RNA, Messenger; D051785:Smad Proteins; D004921:Erythropoietin; D008156:Luciferases
keywords: Hepcidin; High altitude; Huh-7; Hypoxia; Iron