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.

Hypoxia induced downregulation of hepcidin is mediated by platelet derived growth factor BB / T., Sonnweber; D., Nachbaur; A., Schroll; M., Nairz; M., Seifert; E., Demetz; D., Haschka; A. M., Mitterstiller; A., Kleinsasser; M., Burtscher; S., Trubsbach; A. T., Murphy; V., Wroblewski; D. R., Witcher; K., Mleczko Sanecka; Vecchi, Chiara; M. U., Muckenthaler; Pietrangelo, Antonello; I., Theurl; G., Weiss. - In: GUT. - ISSN 0017-5749. - STAMPA. - 63:(2014), pp. 1951-1959. [10.1136/gutjnl-2013-305317]

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

VECCHI, Chiara;PIETRANGELO, Antonello;
2014

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.
2014
GUT
63
1951
1959
Hypoxia induced downregulation of hepcidin is mediated by platelet derived growth factor BB / T., Sonnweber; D., Nachbaur; A., Schroll; M., Nairz; M., Seifert; E., Demetz; D., Haschka; A. M., Mitterstiller; A., Kleinsasser; M., Burtscher; S., Trubsbach; A. T., Murphy; V., Wroblewski; D. R., Witcher; K., Mleczko Sanecka; Vecchi, Chiara; M. U., Muckenthaler; Pietrangelo, Antonello; I., Theurl; G., Weiss. - In: GUT. - ISSN 0017-5749. - STAMPA. - 63:(2014), pp. 1951-1959. [10.1136/gutjnl-2013-305317]
T., Sonnweber; D., Nachbaur; A., Schroll; M., Nairz; M., Seifert; E., Demetz; D., Haschka; A. M., Mitterstiller; A., Kleinsasser; M., Burtscher; S., Trubsbach; A. T., Murphy; V., Wroblewski; D. R., Witcher; K., Mleczko Sanecka; Vecchi, Chiara; M. U., Muckenthaler; Pietrangelo, Antonello; I., Theurl; G., Weiss
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