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Hypoxia induced downregulation of hepcidin is mediated by platelet derived growth factor BB.
- Source :
-
Gut [Gut] 2014 Dec; Vol. 63 (12), pp. 1951-9. Date of Electronic Publication: 2014 Mar 05. - Publication Year :
- 2014
-
Abstract
- Objective: Hypoxia affects body iron homeostasis; however, the underlying mechanisms are incompletely understood.<br />Design: Using a standardised hypoxia chamber, 23 healthy volunteers were subjected to hypoxic conditions, equivalent to an altitude of 5600 m, for 6 h. Subsequent experiments were performed in C57BL/6 mice, CREB-H knockout mice, primary hepatocytes and HepG2 cells.<br />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.<br />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.<br /> (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)
- Subjects :
- Adult
Animals
Becaplermin
Disease Models, Animal
Down-Regulation
Erythropoiesis physiology
Female
Healthy Volunteers
Hematologic Agents pharmacology
Hep G2 Cells
Humans
Hypoxia etiology
Male
Mice
Mice, Inbred C57BL
Hepcidins metabolism
Hypoxia metabolism
Iron metabolism
Platelet-Derived Growth Factor metabolism
Proto-Oncogene Proteins c-sis pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1468-3288
- Volume :
- 63
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Gut
- Publication Type :
- Academic Journal
- Accession number :
- 24598129
- Full Text :
- https://doi.org/10.1136/gutjnl-2013-305317