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Hypoxia induced downregulation of hepcidin is mediated by platelet derived growth factor BB.

Authors
  • Sonnweber, Thomas1
  • Nachbaur, David2
  • Schroll, Andrea1
  • Nairz, Manfred1
  • Seifert, Markus1
  • Demetz, Egon1
  • Haschka, David1
  • Mitterstiller, Anna-Maria1
  • Kleinsasser, Axel3
  • Burtscher, Martin4
  • Trübsbach, Susanne3
  • Murphy, Anthony T5
  • Wroblewski, Victor5
  • Witcher, Derrick R5
  • Mleczko-Sanecka, Katarzyna6
  • Vecchi, Chiara7
  • Muckenthaler, Martina U6
  • Pietrangelo, Antonello7
  • Theurl, Igor1
  • Weiss, Günter1
  • 1 Department of Internal Medicine VI, Medical University Innsbruck, Innsbruck, Austria. , (Austria)
  • 2 Department of Internal Medicine V, Medical University Innsbruck, Innsbruck, Austria. , (Austria)
  • 3 Department of Anaesthesia and Intensive Care Medicine, Medical University Innsbruck, Innsbruck, Austria. , (Austria)
  • 4 Department of Sports Medicine, Leopold-Franzens University, Innsbruck, Austria. , (Austria)
  • 5 Biotechnology Discovery Research, Lilly Research Laboratories, Indianapolis, Indiana, USA. , (India)
  • 6 Department of Pediatric Oncology, Haematology and Immunology, University Hospital of Heidelberg, Heidelberg, Germany. , (Germany)
  • 7 Division of Internal Medicine 2 and Center for Hemochromatosis, "Mario Coppo" Liver Research Center, University Hospital of Modena, Modena, Italy. , (Italy)
Type
Published Article
Journal
Gut
Publisher
BMJ
Publication Date
Dec 01, 2014
Volume
63
Issue
12
Pages
1951–1959
Identifiers
DOI: 10.1136/gutjnl-2013-305317
PMID: 24598129
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Hypoxia affects body iron homeostasis; however, the underlying mechanisms are incompletely understood. 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. 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. 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. 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.

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