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1 National Health and Environmental Effects Research Laboratory, Office of Research and Development, Environmental Protection Agency, Research Triangle Park 27711; 2 Center for Environmental Medicine and Lung Biology, University of North Carolina, Chapel Hill 27599; 3 Department of Biochemistry, State University of New York, Buffalo, New York 14214; 4 Department of Internal Medicine, Duke University Medical Center, Durham, North Carolina 27710; and 5 Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas 78284
Despite a lack of transferrin,
hypotransferrinemic (Hp) mice demonstrate an accumulation of iron in
peripheral organs including the lungs. One potential candidate for such
transferrin-independent uptake of iron is divalent metal transporter-1
(DMT1), an established iron transporter. We tested the hypothesis that
increased concentrations of iron in the lungs of Hp mice are associated
with elevations in DMT1 expression. With the use of inductively coupled
plasma emission spectroscopy, measurements of nonheme iron confirmed significantly elevated concentrations in the lung tissue of Hp mice
relative to the wild-type mice. Western blot analyses for the
expression of two isoforms of DMT1 in the Hp mice relative to the
wild-type animals demonstrated an elevation for the isoform that lacks
an iron-responsive element (IRE) with significant decrements in the
expression of +IRE DMT1. With the use of immunohistochemistry, 
IRE
DMT1 was localized to both airway epithelial cells and alveolar macrophages in wild-type mice. Staining appeared increased in both
types of cells in the Hp mice. Elevated concentrations of both tissue
nonheme iron and expression of IRE DMT1 in the Hp mice were
associated with increased quantities of IRE mRNA. There was no
difference between wild-type and homozygotic Hp mice in the amount of
mRNA for DMT1 +IRE. We conclude that differences between Hp and
wild-type mice in nonheme iron concentrations were accompanied by
increases in the expression of IRE DMT1. Increased expression of
IRE DMT1 in the lungs of the Hp mice could be responsible for
elevated concentrations of the metal in these tissues.
iron transport; transferrin; membrane transporters
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