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Ca2+ channel blockers reverse iron overload by a new mechanism via divalent metal transporter-1

Nature Medicine volume 13, pages 448–454 (2007)Cite this article

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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Figure 1: Nifedipine augments cellular iron uptake via DMT-1.
Figure 2: Patch-clamp analysis of effects of nifedipine on DMT-1–mediated divalent metal transport.
Figure 3: Nifedipine induces duodenal iron accumulation and mobilizes iron from overloaded livers.
Figure 4: Effects of nifedipine treatment on kidney iron distribution, urinary iron excretion and serum iron concentrations.
Figure 5: Effects of nifedipine treatment on liver Hamp1 expression in iron-overloaded mice, and on serum iron concentrations in wild-type and Slc11a2mk/+ mice.

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References

  1. Anderson, G.J. & Powell, L.W. HFE and non-HFE hemochromatosis. Int. J. Hematol. 76, 203–207 (2002).

    Article  Google Scholar 

  2. Fleming, R.E. & Sly, W.S. Mechanisms of iron accumulation in hereditary hemochromatosis. Annu. Rev. Physiol. 64, 663–680 (2002).

    Article  CAS  Google Scholar 

  3. Pietrangelo, A. Hereditary hemochromatosis–a new look at an old disease. N. Engl. J. Med. 350, 2383–2397 (2004).

    Article  CAS  Google Scholar 

  4. Feder, J.N. et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat. Genet. 13, 399–408 (1996).

    Article  CAS  Google Scholar 

  5. Zoller, H., Pietrangelo, A., Vogel, W. & Weiss, G. Duodenal metal-transporter (DMT-1, NRAMP-2) expression in patients with hereditary haemochromatosis. Lancet 353, 2120–2123 (1999).

    Article  CAS  Google Scholar 

  6. Kushner, J.P., Porter, J.P. & Olivieri, N.F. Secondary iron overload. Hematology Am. Soc. Hematol. Educ. Program 47–61 (2001).

  7. Hershko, C., Link, G. & Cabantchik, I. Pathophysiology of iron overload. Ann. NY Acad. Sci. 850, 191–201 (1998).

    Article  CAS  Google Scholar 

  8. Morgan, E.H. & Oates, P.S. Mechanisms and regulation of intestinal iron absorption. Blood Cells Mol. Dis. 29, 384–399 (2002).

    Article  CAS  Google Scholar 

  9. Frazer, D.M. & Anderson, G.J. The orchestration of body iron intake: how and where do enterocytes receive their cues? Blood Cells Mol. Dis. 30, 288–297 (2003).

    Article  CAS  Google Scholar 

  10. Hentze, M.W., Muckenthaler, M.U. & Andrews, N.C. Balancing acts: molecular control of mammalian iron metabolism. Cell 117, 285–297 (2004).

    Article  CAS  Google Scholar 

  11. Kaplan, J. Mechanisms of cellular iron acquisition: another iron in the fire. Cell 111, 603–606 (2002).

    Article  CAS  Google Scholar 

  12. McKie, A.T. et al. An iron-regulated ferric reductase associated with the absorption of dietary iron. Science 291, 1755–1759 (2001).

    Article  CAS  Google Scholar 

  13. Fleming, M.D. et al. Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat. Genet. 16, 383–386 (1997).

    Article  CAS  Google Scholar 

  14. Gunshin, H. et al. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 388, 482–488 (1997).

    Article  CAS  Google Scholar 

  15. Donovan, A. et al. Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 403, 776–781 (2000).

    Article  CAS  Google Scholar 

  16. McKie, A.T. et al. A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol. Cell 5, 299–309 (2000).

    Article  CAS  Google Scholar 

  17. Abboud, S. & Haile, D.J. A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J. Biol. Chem. 275, 19906–19912 (2000).

    Article  CAS  Google Scholar 

  18. Vulpe, C.D. et al. Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nat. Genet. 21, 195–199 (1999).

    Article  CAS  Google Scholar 

  19. Nemeth, E. et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306, 2090–2093 (2004).

    Article  CAS  Google Scholar 

  20. Andrews, N.C. The iron transporter DMT1. Int. J. Biochem. Cell Biol. 31, 991–994 (1999).

    Article  CAS  Google Scholar 

  21. Gunshin, H. et al. Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver. J. Clin. Invest. 115, 1258–1266 (2005).

    Article  CAS  Google Scholar 

  22. Fleming, M.D. et al. Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport. Proc. Natl. Acad. Sci. USA 95, 1148–1153 (1998).

    Article  CAS  Google Scholar 

  23. Xu, H., Jin, J., DeFelice, L.J., Andrews, N.C. & Clapham, D.E. A spontaneous, recurrent mutation in divalent metal transporter-1 exposes a calcium entry pathway. PLoS Biol. 2, E50 (2004).

    Article  Google Scholar 

  24. Hubert, N. & Hentze, M.W. Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: implications for regulation and cellular function. Proc. Natl. Acad. Sci. USA 99, 12345–12350 (2002).

    Article  CAS  Google Scholar 

  25. Ganz, T. Hepcidin–a regulator of intestinal iron absorption and iron recycling by macrophages. Best Pract. Res. Clin. Haematol. 18, 171–182 (2005).

    Article  CAS  Google Scholar 

  26. Muckenthaler, M. et al. Relationships and distinctions in iron-regulatory networks responding to interrelated signals. Blood 101, 3690–3698 (2003).

    Article  CAS  Google Scholar 

  27. Russell, E.S., McFarland, E.C. & Kent, E.L. Low viability, skin lesions, and reduced fertility associated with microcytic anemia in the mouse. Transplant. Proc. 2, 144–151 (1970).

    CAS  PubMed  Google Scholar 

  28. Mackenzie, B., Ujwal, M.L., Chang, M.H., Romero, M.F. & Hediger, M.A. Divalent metal-ion transporter DMT1 mediates both H(+) -coupled Fe(2+) transport and uncoupled fluxes. Pflugers Arch. 451, 544–558 (2006).

    Article  CAS  Google Scholar 

  29. Lam-Yuk-Tseung, S. & Gros, P. Distinct targeting and recycling properties of two isoforms of the iron transporter DMT1 (NRAMP2, Slc11A2). Biochemistry 45, 2294–2301 (2006).

    Article  CAS  Google Scholar 

  30. Oudit, G.Y. et al. L-type Ca2+ channels provide a major pathway for iron entry into cardiomyocytes in iron-overload cardiomyopathy. Nat. Med. 9, 1187–1194 (2003).

    Article  CAS  Google Scholar 

  31. Musilkova, J. & Kovar, J. Additive stimulatory effect of extracellular calcium and potassium on non-transferrin ferric iron uptake by HeLa and K562 cells. Biochim. Biophys. Acta 1514, 117–126 (2001).

    Article  CAS  Google Scholar 

  32. Hockerman, G.H., Peterson, B.Z., Johnson, B.D. & Catterall, W.A. Molecular determinants of drug binding and action on L-type calcium channels. Annu. Rev. Pharmacol. Toxicol. 37, 361–396 (1997).

    Article  CAS  Google Scholar 

  33. Striessnig, J. Pharmacology, structure and function of cardiac L-type Ca(2+) channels. Cell. Physiol. Biochem. 9, 242–269 (1999).

    Article  CAS  Google Scholar 

  34. Zhou, X.Y. et al. HFE gene knockout produces mouse model of hereditary hemochromatosis. Proc. Natl. Acad. Sci. USA 95, 2492–2497 (1998).

    Article  CAS  Google Scholar 

  35. Bahram, S. et al. Experimental hemochromatosis due to MHC class I HFE deficiency: immune status and iron metabolism. Proc. Natl. Acad. Sci. USA 96, 13312–13317 (1999).

    Article  CAS  Google Scholar 

  36. Iolascon, A. et al. Microcytic anemia and hepatic iron overload in a child with compound heterozygous mutations in DMT1 (SCL11A2). Blood 107, 349–354 (2006).

    Article  CAS  Google Scholar 

  37. Mims, M.P. et al. Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload. Blood 105, 1337–1342 (2005).

    Article  CAS  Google Scholar 

  38. Beaumont, C. et al. Two new human DMT1 gene mutations in a patient with microcytic anemia, low ferritinemia, and liver iron overload. Blood 107, 4168–4170 (2006).

    Article  CAS  Google Scholar 

  39. Ferguson, C.J. et al. Cellular localization of divalent metal transporter DMT-1 in rat kidney. Am. J. Physiol. Renal Physiol. 280, F803–F814 (2001).

    Article  CAS  Google Scholar 

  40. Canonne-Hergaux, F. & Gros, P. Expression of the iron transporter DMT1 in kidney from normal and anemic mk mice. Kidney Int. 62, 147–156 (2002).

    Article  CAS  Google Scholar 

  41. Abouhamed, M. et al. Divalent metal transporter 1 in the kidney proximal tubule is expressed in late endosomes/lysosomal membranes: implications for renal handling of protein-metal complexes. Am. J. Physiol. Renal Physiol. 290, F1525–F1533 (2006).

    Article  CAS  Google Scholar 

  42. Wareing, M. et al. Altered dietary iron intake is a strong modulator of renal DMT1 expression. Am. J. Physiol. Renal Physiol. 285, F1050–F1059 (2003).

    Article  CAS  Google Scholar 

  43. Gruen, A.B., Zhou, J., Morton, K.A. & Milstone, L.M. Photodegraded nifedipine stimulates uptake and retention of iron in human epidermal keratinocytes. J. Invest. Dermatol. 116, 774–777 (2001).

    Article  CAS  Google Scholar 

  44. Savigni, D.L., Wege, D., Cliff, G.S., Meesters, M.L. & Morgan, E.H. Iron and transition metal transport into erythrocytes mediated by nifedipine degradation products and related compounds. Biochem. Pharmacol. 65, 1215–1226 (2003).

    Article  CAS  Google Scholar 

  45. Mims, M.P. & Prchal, J.T. Divalent metal transporter 1. Hematology 10, 339–345 (2005).

    Article  CAS  Google Scholar 

  46. Ludwiczek, S., Theurl, I., Artner-Dworzak, E., Chorney, M. & Weiss, G. Duodenal HFE expression and hepcidin levels determine body iron homeostasis: modulation by genetic diversity and dietary iron availability. J. Mol. Med. 82, 373–382 (2004).

    Article  CAS  Google Scholar 

  47. Ludwiczek, S., Aigner, E., Theurl, I. & Weiss, G. Cytokine-mediated regulation of iron transport in human monocytic cells. Blood 101, 4148–4154 (2003).

    Article  CAS  Google Scholar 

Download references

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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Authors and Affiliations

  1. Department of General Internal Medicine, Clinical Immunology and Infectious Diseases, Innsbruck Medical University, Anichstr. 35, Innsbruck, A-6020, Austria

    Susanne Ludwiczek, Igor Theurl, Sabine M Mair, Milan Theurl & Guenter Weiss

  2. Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Im Neuenheimer Feld 153, Heidelberg, D-69120, Germany

    Martina U Muckenthaler & Judit Kiss

  3. Department of Physiology and Medial Physics, Innsbruck Medical University, Fritz-Pregl Str. 3, Innsbruck, A-6020, Austria

    Martin Jakab, Markus Paulmichl & Markus Ritter

  4. Institute of Physiology, Paracelsus Medical University, Strubergasse 21, Salzburg, A-5020, Austria

    Martin Jakab & Markus Ritter

  5. Department of Biomolecular Sciences and Biotechnology, Universita degli Studi di Milano, Via Celoria 26, Milano, I-20133, Italy

    Markus Paulmichl

  6. European Molecular Laboratory (EMBL), Gene Expression Unit, Meyerhofstr. 1, Heidelberg, D-69117, Germany

    Matthias W Hentze

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Contributions

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.

Corresponding authors

Correspondence to Matthias W Hentze or Guenter Weiss.

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The authors declare no competing financial interests.

Supplementary information

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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