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Blood, 1 April 2006, Vol. 107, No. 7, pp. 2952-2958.
Prepublished online as a Blood First Edition Paper on December 8, 2005; DOI 10.1182/blood-2005-10-4071.
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RED CELLS
Chronic hepcidin induction causes hyposideremia and alters the pattern of cellular iron accumulation in hemochromatotic mice
Lydie Viatte,
Gaël Nicolas,
Dan-Qing Lou,
Myriam Bennoun,
Jeanne-Claire Lesbordes-Brion,
François Canonne-Hergaux,
Kai Schönig,
Hermann Bujard,
Axel Kahn,
Nancy C. Andrews, and
Sophie Vaulont
From the Institut Cochin, Département de Génétique, Développement et Pathologie Moléculaire, Paris; Institut National de la Santé et de la Recherche Médicale (INSERM) U567, Centre National de Recherche Scientifique (CNRS) Unité mixte de Recherche (UMR) 8104, Université Paris Descartes, Faculté de Médecine René Descartes, UMR-S 8104, Paris; Institut National de la Transfusion Sanguine, Inserm U665, Paris; Inserm U409, Faculté deMédecine Xavier Bichat, Paris, France; Zentrum für Molekuläre Biologie, Heidelberg, Germany; and Children's Hospital Boston, Dana-Farber Cancer Institute, Harvard Medical School, Howard Hughes Medical Institute, Boston, MA.
We report the generation of a tetracycline-regulated (Tet ON) transgenic mouse model for acute and chronic expression of the iron regulatory peptide hepcidin in the liver. We demonstrate that short-term and long-term tetracycline-dependent activation of hepcidin in adult mice leads to hypoferremia and iron-limited erythropoiesis, respectively. This clearly establishes the key role of hepcidin in regulating the extracellular iron concentration. We previously demonstrated that, when expressed early in fetal development, constitutive transgenic hepcidin expression prevented iron accumulation in an Hfe-/- mouse model of hemochromatosis. We now explore the effect of chronic hepcidin expression in adult Hfe-/- mice that have already developed liver iron overload. We demonstrate that induction of chronic hepcidin expression in 2-month-old Hfe-/- mice alters their pattern of cellular iron accumulation, leading to increased iron in tissue macrophages and duodenal cells but less iron in hepatocytes. These hepcidin-induced changes in the pattern of cellular iron accumulation are associated with decreased expression of the iron exporter ferroportin in macrophages but no detectable alteration of ferroportin expression in the hepatocytes. We speculate that this change in iron homeostasis could offer a therapeutic advantage by protecting against damage to parenchymal cells.
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