Hypoxia induced downregulation of hepcidin is mediated by platelet derived growth factor BB.
Gut
; 63(12): 1951-9, 2014 Dec.
Article
em En
| MEDLINE
| ID: mdl-24598129
ABSTRACT
OBJECTIVE:
Hypoxia affects body iron homeostasis; however, the underlying mechanisms are incompletely understood.DESIGN:
Using a standardised hypoxia chamber, 23 healthy volunteers were subjected to hypoxic conditions, equivalent to an altitude of 5600â m, for 6â h. Subsequent experiments were performed in C57BL/6 mice, CREB-H knockout mice, primary hepatocytes and HepG2 cells.RESULTS:
Exposure of subjects to hypoxia resulted in a significant decrease of serum levels of the master regulator of iron homeostasis hepcidin and elevated concentrations of platelet derived growth factor (PDGF)-BB. Using correlation analysis, we identified PDGF-BB to be associated with hypoxia mediated hepcidin repression in humans. We then exposed mice to hypoxia using a standardised chamber and observed downregulation of hepatic hepcidin mRNA expression that was paralleled by elevated serum PDGF-BB protein concentrations and higher serum iron levels as compared with mice housed under normoxic conditions. PDGF-BB treatment in vitro and in vivo resulted in suppression of both steady state and BMP6 inducible hepcidin expression. Mechanistically, PDGF-BB inhibits hepcidin transcription by downregulating the protein expression of the transcription factors CREB and CREB-H, and pharmacological blockade or genetic ablation of these pathways abrogated the effects of PDGF-BB toward hepcidin expression.CONCLUSIONS:
Hypoxia decreases hepatic hepcidin expression by a novel regulatory pathway exerted via PDGF-BB, leading to increased availability of circulating iron that can be used for erythropoiesis.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fator de Crescimento Derivado de Plaquetas
/
Proteínas Proto-Oncogênicas c-sis
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Hepcidinas
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Ferro
/
Hipóxia
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
Limite:
Adult
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Animals
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article