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Hypoxia induced downregulation of hepcidin is mediated by platelet derived growth factor BB
  1. Thomas Sonnweber1,
  2. David Nachbaur2,
  3. Andrea Schroll1,
  4. Manfred Nairz1,
  5. Markus Seifert1,
  6. Egon Demetz1,
  7. David Haschka1,
  8. Anna-Maria Mitterstiller1,
  9. Axel Kleinsasser3,
  10. Martin Burtscher4,
  11. Susanne Trübsbach3,
  12. Anthony T Murphy5,
  13. Victor Wroblewski5,
  14. Derrick R Witcher5,
  15. Katarzyna Mleczko-Sanecka6,
  16. Chiara Vecchi7,
  17. Martina U Muckenthaler6,
  18. Antonello Pietrangelo7,
  19. Igor Theurl1,
  20. Günter Weiss1
  1. 1Department of Internal Medicine VI, Medical University Innsbruck, Innsbruck, Austria
  2. 2Department of Internal Medicine V, Medical University Innsbruck, Innsbruck, Austria
  3. 3Department of Anaesthesia and Intensive Care Medicine, Medical University Innsbruck, Innsbruck, Austria
  4. 4Department of Sports Medicine, Leopold-Franzens University, Innsbruck, Austria
  5. 5Biotechnology Discovery Research, Lilly Research Laboratories, Indianapolis, Indiana, USA
  6. 6Department of Pediatric Oncology, Haematology and Immunology, University Hospital of Heidelberg, Heidelberg, Germany
  7. 7Division of Internal Medicine 2 and Center for Hemochromatosis, “Mario Coppo” Liver Research Center, University Hospital of Modena, Modena, Italy
  1. Correspondence to Professors Guenter Weiss and Igor Theurl, Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology, Anichstrasse 35, Medical University Innsbruck, Innsbruck A-6020, Austria; igor.theurl{at}i-med.ac.at or guenter.weiss{at}i-med.ac.at

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 5600 m, for 6 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.

  • IRON METABOLISM
  • OXIDATIVE METABOLISM

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