PT  - JOURNAL ARTICLE
AU  - Thomas Sonnweber
AU  - David Nachbaur
AU  - Andrea Schroll
AU  - Manfred Nairz
AU  - Markus Seifert
AU  - Egon Demetz
AU  - David Haschka
AU  - Anna-Maria Mitterstiller
AU  - Axel Kleinsasser
AU  - Martin Burtscher
AU  - Susanne Trübsbach
AU  - Anthony T Murphy
AU  - Victor Wroblewski
AU  - Derrick R Witcher
AU  - Katarzyna Mleczko-Sanecka
AU  - Chiara Vecchi
AU  - Martina U Muckenthaler
AU  - Antonello Pietrangelo
AU  - Igor Theurl
AU  - Günter Weiss
TI  - Hypoxia induced downregulation of hepcidin is mediated by platelet derived growth factor BB
AID  - 10.1136/gutjnl-2013-305317
DP  - 2014 Dec 01
TA  - Gut
PG  - 1951--1959
VI  - 63
IP  - 12
4099  - http://gut.bmj.com/content/63/12/1951.short
4100  - http://gut.bmj.com/content/63/12/1951.full
SO  - Gut2014 Dec 01; 63
AB  - 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.