Minihepcidins prevent iron overload in a hepcidin-deficient mouse model of severe hemochromatosis

被引:185
作者
Ramos, Emilio [2 ]
Ruchala, Piotr [1 ]
Goodnough, Julia B. [1 ]
Kautz, Leon [1 ]
Preza, Gloria C. [3 ]
Nemeth, Elizabeta [1 ]
Ganz, Tomas [1 ,4 ]
机构
[1] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA
[2] Univ Calif Los Angeles, David Geffen Sch Med, Dept Chem & Biochem, Los Angeles, CA 90095 USA
[3] Univ So Calif, Keck Sch Med, Dept Dermatol, Los Angeles, CA 90033 USA
[4] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol, Los Angeles, CA 90095 USA
基金
美国国家卫生研究院;
关键词
MICE; THALASSEMIA; DISORDERS; INSULIN;
D O I
10.1182/blood-2012-07-440743
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The deficiency of hepcidin, the hormone that controls iron absorption and its tissue distribution, is the cause of iron overload in nearly all forms of hereditary hemochromatosis and in untransfused iron-loading anemias. In a recent study, we reported the development of minihepcidins, small drug-like hepcidin agonists. Here we explore the feasibility of using minihepcidins for the prevention and treatment of iron overload in hepcidin-deficient mice. An optimized minihepcidin (PR65) was developed that had superior potency and duration of action compared with natural hepcidin or other minihepcidins, and favorable cost of synthesis. PR65 was administered by subcutaneous injection daily for 2 weeks to iron-depleted or iron-loaded hepcidin knockout mice. PR65 administration to iron-depleted mice prevented liver iron loading, decreased heart iron levels, and caused the expected iron retention in the spleen and duodenum. At high doses, PR65 treatment also caused anemia because of profound iron restriction. PR65 administration to hepcidin knockout mice with pre-existing iron overload had a more moderate effect and caused partial redistribution of iron from the liver to the spleen. Our study demonstrates that minihepcidins could be beneficial in iron overload disorders either used alone for prevention or possibly as adjunctive therapy with phlebotomy or chelation. (Blood.2012;120(18):3829-3836)
引用
收藏
页码:3829 / 3836
页数:8
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