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

• Published in: Gut Vol. 63; no. 12; pp. 1951 - 1959
• Main Authors: Sonnweber, Thomas, Nachbaur, David, Schroll, Andrea, Nairz, Manfred, Seifert, Markus, Demetz, Egon, Haschka, David, Mitterstiller, Anna-Maria, Kleinsasser, Axel, Burtscher, Martin, Trübsbach, Susanne, Murphy, Anthony T, Wroblewski, Victor, Witcher, Derrick R, Mleczko-Sanecka, Katarzyna, Vecchi, Chiara, Muckenthaler, Martina U, Pietrangelo, Antonello, Theurl, Igor, Weiss, Günter
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.12.2014
• Subjects: Adult; Animals; Becaplermin; Cell culture; Disease Models, Animal; Down-Regulation; Erythropoiesis - physiology; Experiments; Female; Growth factors; Healthy Volunteers; Hematologic Agents - pharmacology; Hep G2 Cells; Hepcidins - metabolism; Homeostasis; Humans; Hypoxia; Hypoxia - etiology; Hypoxia - metabolism; Iron; Iron - metabolism; Kinases; Male; Metabolism; Mice; Mice, Inbred C57BL; Platelet-Derived Growth Factor - metabolism; Proteins; Proto-Oncogene Proteins c-sis - pharmacology; Rodents; Studies; IRON METABOLISM; OXIDATIVE METABOLISM
• ISSN: 0017-5749; 1468-3288
• DOI: 10.1136/gutjnl-2013-305317

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.