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

ABSTRACT: Excessive iron absorption is one of the main features of ?-thalassemia and can lead to severe morbidity and mortality. Serial analyses of ?-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 ?-thalassemia also have low hepcidin levels. These observations led us to hypothesize that more iron is absorbed in ?-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 ?-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 ?-thalassemia and related disorders.

SUBMITTER: Gardenghi S

PROVIDER: S-EPMC2993583 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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

Gardenghi Sara S Ramos Pedro P Marongiu Maria Franca MF Melchiori Luca L Breda Laura L Guy Ella E Muirhead Kristen K Rao Niva N Roy Cindy N CN Andrews Nancy C NC Nemeth Elizabeta E Follenzi Antonia A An Xiuli X Mohandas Narla N Ginzburg Yelena Y Rachmilewitz Eliezer A EA Giardina Patricia J PJ Grady Robert W RW Rivella Stefano S

The Journal of clinical investigation 20101122 12

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 ...[more]

PMID: 21099112

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Project description:Systemic iron levels must be maintained in physiological concentrations to prevent diseases associated with iron deficiency or iron overload. A key role in this process plays ferroportin, the only known mammalian transmembrane iron exporter, which releases iron from duodenal enterocytes, hepatocytes, or iron-recycling macrophages into the blood stream. Ferroportin expression is tightly controlled by transcriptional and post-transcriptional mechanisms in response to hypoxia, iron deficiency, heme iron and inflammatory cues by cell-autonomous and systemic mechanisms. At the systemic level, the iron-regulatory hormone hepcidin is released from the liver in response to these cues, binds to ferroportin and triggers its degradation. The relative importance of individual ferroportin control mechanisms and their interplay at the systemic level is incompletely understood. Here, we built a mathematical model of systemic iron regulation. It incorporates the dynamics of organ iron pools as well as regulation by the hepcidin/ferroportin system. We calibrated and validated the model with time-resolved measurements of iron responses in mice challenged with dietary iron overload and/or inflammation. The model demonstrates that inflammation mainly reduces the amount of iron in the blood stream by reducing intracellular ferroportin transcription, and not by hepcidin-dependent ferroportin protein destabilization. In contrast, ferroportin regulation by hepcidin is the predominant mechanism of iron homeostasis in response to changing iron diets for a big range of dietary iron contents. The model further reveals that additional homeostasis mechanisms must be taken into account at very high dietary iron levels, including the saturation of intestinal uptake of nutritional iron and the uptake of circulating, non-transferrin-bound iron, into liver. Taken together, our model quantitatively describes systemic iron metabolism and generated experimentally testable predictions for additional ferroportin-independent homeostasis mechanisms.

Dataset Information

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

Publications

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

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