title: Hypoxia induced downregulation of hepcidin is mediated by platelet derived growth factor BB.
abstract: OBJECTIVE
  Hypoxia affects body iron homeostasis; however, the underlying mechanisms are incompletely understood.
  
  
  METHODS
  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.
authors.affiliation: Department of Internal Medicine VI, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Sonnweber
authors.affiliation: Department of Internal Medicine V, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: David
authors.initials: D
authors.lastname: Nachbaur
authors.affiliation: Department of Internal Medicine VI, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schroll
authors.affiliation: Department of Internal Medicine VI, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Manfred
authors.initials: M
authors.lastname: Nairz
authors.affiliation: Department of Internal Medicine VI, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Seifert
authors.affiliation: Department of Internal Medicine VI, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Egon
authors.initials: E
authors.lastname: Demetz
authors.affiliation: Department of Internal Medicine VI, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: David
authors.initials: D
authors.lastname: Haschka
authors.affiliation: Department of Internal Medicine VI, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Mitterstiller
authors.affiliation: Department of Anaesthesia and Intensive Care Medicine, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Axel
authors.initials: A
authors.lastname: Kleinsasser
authors.affiliation: Department of Sports Medicine, Leopold-Franzens University, Innsbruck, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Burtscher
authors.affiliation: Department of Anaesthesia and Intensive Care Medicine, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Susanne
authors.initials: S
authors.lastname: Trübsbach
authors.affiliation: Biotechnology Discovery Research, Lilly Research Laboratories, Indianapolis, Indiana, USA.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Murphy
authors.affiliation: Biotechnology Discovery Research, Lilly Research Laboratories, Indianapolis, Indiana, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Wroblewski
authors.affiliation: Biotechnology Discovery Research, Lilly Research Laboratories, Indianapolis, Indiana, USA.
authors.forename: Derrick R
authors.initials: DR
authors.lastname: Witcher
authors.affiliation: Department of Pediatric Oncology, Haematology and Immunology, University Hospital of Heidelberg, Heidelberg, Germany.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Mleczko-Sanecka
authors.affiliation: Division of Internal Medicine 2 and Center for Hemochromatosis, "Mario Coppo" Liver Research Center, University Hospital of Modena, Modena, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Vecchi
authors.affiliation: Department of Pediatric Oncology, Haematology and Immunology, University Hospital of Heidelberg, Heidelberg, Germany.
authors.forename: Martina U
authors.initials: MU
authors.lastname: Muckenthaler
authors.affiliation: Division of Internal Medicine 2 and Center for Hemochromatosis, "Mario Coppo" Liver Research Center, University Hospital of Modena, Modena, Italy.
authors.forename: Antonello
authors.initials: A
authors.lastname: Pietrangelo
authors.affiliation: Department of Internal Medicine VI, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Igor
authors.initials: I
authors.lastname: Theurl
authors.affiliation: Department of Internal Medicine VI, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Günter
authors.initials: G
authors.lastname: Weiss
mesh_terms: D000328:Adult; D000818:Animals; D000077214:Becaplermin; D004195:Disease Models, Animal; D015536:Down-Regulation; D004920:Erythropoiesis / Q000502:physiology; D005260:Female; D064368:Healthy Volunteers; D006401:Hematologic Agents / Q000494:pharmacology; D056945:Hep G2 Cells; D064451:Hepcidins / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000209:etiology / Q000378:metabolism*; D007501:Iron / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology*
chemical_list: D006401:Hematologic Agents; D064451:Hepcidins; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D007501:Iron
keywords: IRON METABOLISM; OXIDATIVE METABOLISM