Abstract
Hereditary hemochromatosis and transfusional iron overload are frequent clinical conditions associated with progressive iron accumulation in parenchymal tissues, leading to eventual organ failure. We have discovered a new mechanism to reverse iron overload—pharmacological modulation of the divalent metal transporter-1 (DMT-1). DMT-1 mediates intracellular iron transport during the transferrin cycle and apical iron absorption in the duodenum. Its additional functions in iron handling in the kidney and liver are less well understood. We show that the L-type calcium channel blocker nifedipine increases DMT-1–mediated cellular iron transport 10- to 100-fold at concentrations between 1 and 100 μM. Mechanistically, nifedipine causes this effect by prolonging the iron-transporting activity of DMT-1. We show that nifedipine mobilizes iron from the liver of mice with primary and secondary iron overload and enhances urinary iron excretion. Modulation of DMT-1 function by L-type calcium channel blockers emerges as a new pharmacological therapy for the treatment of iron overload disorders.
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Acknowledgements
The authors thank S. Bahram (University of Strasbourg) and K. Schuemann (Munich Technical University) for providing Hfe−/− mice, and L. Montross, H. Gunshin and N. Andrews (Harvard Medical School) for their gift of heterozygous mk mice. We thank P. Gros (McGill University) for providing the DMT-1 antibody. We also thank J. Striessnig for discussions. This work was supported by the Austrian Research Funds (projects P15943 and P19664 to G.W.).
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S.L. performed and designed cell culture, drug screening and animal experiments, analyzed data and generated figures. I.T. performed cell culture, animal experiments and histological examinations. M.U.M. designed and analyzed experiments, interpreted data and wrote the manuscript. M.J. performed electrophysiology experiments. S.M.M. performed electrophysiology, cell culture and animal experiments with mk mice and generated figures. M.T. performed quantitative RT-PCR. J.K. contributed to the analysis of mk mice. M.P. designed and interpreted electrophysiology experiments and edited the paper. M.W.H. designed experiments, interpreted data and wrote the manuscript. M.R. designed and interpreted electrophysiology experiments and edited the paper. G.W. designed the study and experiments, analyzed and interpreted data and wrote the manuscript.
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Supplementary Table 1
Summary of the liver regulatory responses to nifedipine-treatment of wild-type and Hfe mutant mice and mice subjected to secondary iron overload. (PDF 28 kb)
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Ludwiczek, S., Theurl, I., Muckenthaler, M. et al. Ca2+ channel blockers reverse iron overload by a new mechanism via divalent metal transporter-1. Nat Med 13, 448–454 (2007). https://doi.org/10.1038/nm1542
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DOI: https://doi.org/10.1038/nm1542
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