TITLE

Hepcidin as a therapeutic tool to limit iron overload and improve anemia in β-thalassemic mice

AUTHOR(S)
Gardenghi, Sara; Ramos, Pedro; Marongiu, Maria Franca; Melchiori, Luca; Breda, Laura; Guy, Ella; Muirhead, Kristen; Rao, Niva; Roy, Cindy N.; Andrews, Nancy C.; Nemeth, Elizabeta; Follenzi, Antonia; Xiuli An; Mohandas, Narla; Ginzburg, Yelena; Rachmilewitz, Eliezer A.; Giardina, Patricia J.; Grady, Robert W.; Rivella, Stefano; An, Xiuli
PUB. DATE
December 2010
SOURCE
Journal of Clinical Investigation;Dec2010, Vol. 120 Issue 12, p4466
SOURCE TYPE
Academic Journal
DOC. TYPE
journal article
ABSTRACT
Excessive iron absorption is one of the main features of β-thalassemia and can lead to severe morbidity and mortality. Serial analyses of β-thalassemic mice indicate that while hemoglobin levels decrease over time, the concentration of iron in the liver, spleen, and kidneys markedly increases. Iron overload is associated with low levels of hepcidin, a peptide that regulates iron metabolism by triggering degradation of ferroportin, an iron-transport protein localized on absorptive enterocytes as well as hepatocytes and macrophages. Patients with β-thalassemia also have low hepcidin levels. These observations led us to hypothesize that more iron is absorbed in β-thalassemia than is required for erythropoiesis and that increasing the concentration of hepcidin in the body of such patients might be therapeutic, limiting iron overload. Here we demonstrate that a moderate increase in expression of hepcidin in β-thalassemic mice limits iron overload, decreases formation of insoluble membrane-bound globins and reactive oxygen species, and improves anemia. Mice with increased hepcidin expression also demonstrated an increase in the lifespan of their red cells, reversal of ineffective erythropoiesis and splenomegaly, and an increase in total hemoglobin levels. These data led us to suggest that therapeutics that could increase hepcidin levels or act as hepcidin agonists might help treat the abnormal iron absorption in individuals with β-thalassemia and related disorders.
ACCESSION #
55792465

 

Related Articles

  • A tincture of hepcidin cures all: the potential for hepcidin therapeutics. Bartnikas, Thomas B.; Fleming, Mark D. // Journal of Clinical Investigation;Dec2010, Vol. 120 Issue 12, p4187 

    Iron overload as a result of blood transfusions and excessive intestinal iron absorption can be a complication of chronic anemias such as β-thalassemia. Inappropriately low levels of hepcidin, a negative regulator of iron absorption and recycling, underlie the pathophysiology of the...

  • Disruption of erythroid K-Cl cotransporters alters erythrocyte volume and partially rescues erythrocyte dehydration in SAD mice. Rust, Marco B.; Alper, Seth L.; Rudhard, York; Shmukler, Boris E.; Vicente, Rubén; Brugnara, Carlo; Trudel, Marie; Jentsch, Thomas J.; Hübner, Christian A.; Vicente, Rubén; Hübner, Christian A // Journal of Clinical Investigation;Jun2007, Vol. 117 Issue 6, p1708 

    K-Cl cotransport activity in rbc is a major determinant of rbc volume and density. Pathologic activation of erythroid K-Cl cotransport activity in sickle cell disease contributes to rbc dehydration and cell sickling. To address the roles of individual K-Cl cotransporter isoforms in rbc volume...

  • LXRβ is required for glucocorticoid-induced hyperglycemia and hepatosteatosis in mice. Patel, Rucha; Patel, Monika; Tsai, Ricky; Lin, Vicky; Bookout, Angie L.; Yuan Zhang; Magomedova, Lilia; Tingting Li; Chan, Jessica F.; Budd, Conrad; Mangelsdorf, David J.; Cummins, Carolyn L.; Zhang, Yuan; Li, Tingting // Journal of Clinical Investigation;Jan2011, Vol. 121 Issue 1, p431 

    Although widely prescribed for their potent antiinflammatory actions, glucocorticoid drugs (e.g., dexamethasone) cause undesirable side effects that are features of the metabolic syndrome, including hyperglycemia, fatty liver, insulin resistance, and type II diabetes. Liver x receptors (LXRs)...

  • The challenge of target sequence specificity in C-->U RNA editing. Davidson, Nicholas O. // Journal of Clinical Investigation;2/1/2002, Vol. 109 Issue 3, p291 

    Discusses links between RNA editing and other co- and post-transcriptional events regulating gene expression. Forms of RNA editing in mammalian cells; Example of C→U RNA editing; Characteristics of RNA-specific cytidine deaminase apobec-1 (4) and apobec-1 complementation factor;...

  • Primary CTL response magnitude in mice is determined by the extent of naive T cell recruitment and subsequent clonal expansion. La Gruta, Nicole L.; Rothwell, William T.; Cukalac, Tania; Swan, Natasha G.; Valkenburg, Sophie A.; Kedzierska, Katherine; Thomas, Paul G.; Doherty, Peter C.; Turner, Stephen J. // Journal of Clinical Investigation;Jun2010, Vol. 120 Issue 6, p1885 

    CD8+ T cell responses to viral infection are characterized by the emergence of dominant and subdominant CTL populations. The immunodominance hierarchies of these populations are highly reproducible for any given spectrum of virus-induced peptide-MHCI complexes and are likely determined by...

  • In vivo expansion of CD4CD45RO-CD25 T cells expressing foxP3 in IL-2-treated HIV-infected patients. Sereti, Irini; Imamichi, Hiromi; Natarajan, Ven; Imamichi, Tomozumi; Ramchandani, Meena S.; Badralmaa, Yunden; Berg, Steve C.; Metcalf, Julia A.; Hahn, Barbara K.; Shen, Jean M.; Powers, April; Davey, Richard T.; Kovacs, Joseph A.; Shevach, Ethan M.; Lane, H. Clifford // Journal of Clinical Investigation;Jul2005, Vol. 115 Issue 7, p1839 

    Administration of IL-2 to HIV-infected patients leads to expansion of a unique subset of CD4CD45ROCD25 cells. In this study, the origin, clonality, and function of these cells were investigated. Analysis of TCR excision circles revealed that the CD4CD45ROCD25 cells were the product of peripheral...

  • Serotonin receptor 1A-modulated phosphorylation of glycine receptor α3 controls breathing in mice. Till Manzke; Niebert, Marcus; Koch, Uwe R.; Caley, Alex; Vogelgesang, Steffen; Hülsmann, Swen; Ponimaskin, Evgeni; Müller, Ulrike; Smart, Trevor G.; Harvey, Robert J.; Richter, Diethelm W.; Manzke, Till; Hülsmann, Swen; Müller, Ulrike // Journal of Clinical Investigation;Nov2010, Vol. 120 Issue 11, p4118 

    Rhythmic breathing movements originate from a dispersed neuronal network in the medulla and pons. Here, we demonstrate that rhythmic activity of this respiratory network is affected by the phosphorylation status of the inhibitory glycine receptor α3 subtype (GlyRα3), which controls...

  • A mouse model of juvenile hemochromatosis. Huang, Franklin W.; Pinkus, Jack L.; Pinkus, Geraldine S.; Fleming, Mark D.; Andrews, Nancy C. // Journal of Clinical Investigation;Aug2005, Vol. 115 Issue 8, p2187 

    Hereditary hemochromatosis is an iron-overload disorder resulting from mutations in proteins presumed to be involved in the maintenance of iron homeostasis. Mutations in hemojuvelin (HJV) cause severe, early-onset juvenile hemochromatosis. The normal function of HJV is unknown. Juvenile...

  • Reliability of the nanopheres-DNA immunization technology to produce polyclonal antibodies directed against human neogenic proteins. Arnaoty, Ahmed; Gouilleux-Gruart, Valérie; Casteret, Sophie; Pitard, Bruno; Bigot, Yves; Lecomte, Thierry // Molecular Genetics & Genomics;Aug2013, Vol. 288 Issue 7/8, p347 

    The molecular domestication of several DNA transposons that occurred during the evolution of the mammalian lineage, has led to the emergence of at least 43 genes, known as neogenes. To date, the limited availability of efficient commercial antibodies directed against most of their protein...

Share

Read the Article

Courtesy of THE LIBRARY OF VIRGINIA

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics