Molecular Mechanisms of Hepcidin Regulation: Implications for the Anemia of CKD

American Journal of Kidney Diseases

Volumn 55, Issue 4, 2010, Pages 726-741

  Babitt, Jodie L ^a   Lin, Herbert Y ^a  

^a Center for Systems Biology   (United States)

Author keywords

Anemia; chronic kidney disease; dialysis; hepcidin; inflammation

Indexed keywords

BONE MORPHOGENETIC PROTEIN 6; HEPCIDIN; IRON; SMAD PROTEIN;

ANEMIA; ARTICLE; CHRONIC KIDNEY DISEASE; HOMEOSTASIS; HUMAN; HYPOXIA; INFLAMMATION; IRON DEFICIENCY; IRON OVERLOAD; MOUSE; NONHUMAN; PATHOGENESIS; PROTEIN EXPRESSION; SIGNAL TRANSDUCTION;

ANEMIA; ANTIMICROBIAL CATIONIC PEPTIDES; CHRONIC DISEASE; FEMALE; HOMEOSTASIS; HUMANS; IRON; KIDNEY DISEASES; MIDDLE AGED;

EID: 77949774448     PISSN: 02726386     EISSN: None     Source Type: Journal    
DOI: 10.1053/j.ajkd.2009.12.030     Document Type: Article

References (149)

1. National Kidney Foundation. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis. 47 5 suppl 3 (2006) S1-S145
2. Besarab A., Bolton W.K., Browne J.K., et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med. 339 9 (1998) 584-590
3. Singh A.K., Szczech L., Tang K.L., et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 355 20 (2006) 2085-2098
4. Szczech L.A., Barnhart H.X., Inrig J.K., et al. Secondary analysis of the CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes. Kidney Int. 74 6 (2008) 791-798
5. Weiss G., and Goodnough L.T. Anemia of chronic disease. N Engl J Med. 352 10 (2005) 1011-1023
6. Malyszko J., and Mysliwiec M. Hepcidin in anemia and inflammation in chronic kidney disease. Kidney Blood Press Res. 30 1 (2007) 15-30
7. Macdougall I.C., Tucker B., Thompson J., Tomson C.R., Baker L.R., and Raine A.E. A randomized controlled study of iron supplementation in patients treated with erythropoietin. Kidney Int. 50 5 (1996) 1694-1699
8. Fudin R., Jaichenko J., Shostak A., Bennett M., and Gotloib L. Correction of uremic iron deficiency anemia in hemodialyzed patients: a prospective study. Nephron 79 3 (1998) 299-305
9. Markowitz G.S., Kahn G.A., Feingold R.E., Coco M., and Lynn R.I. An evaluation of the effectiveness of oral iron therapy in hemodialysis patients receiving recombinant human erythropoietin. Clin Nephrol. 48 1 (1997) 34-40
10. Eleftheriadis T., Antoniadi G., Liakopoulos V., Kartsios C., and Stefanidis I. Disturbances of acquired immunity in hemodialysis patients. Semin Dial. 20 5 (2007) 440-451
11. Ganz T., Olbina G., Girelli D., Nemeth E., and Westerman M. Immunoassay for human serum hepcidin. Blood 112 (2008) 4292-4297
12. Ashby D.R., Gale D.P., Busbridge M., et al. Plasma hepcidin levels are elevated but responsive to erythropoietin therapy in renal disease. Kidney Int. 75 9 (2009) 976-981
13. Zaritsky J., Young B., Wang H.J., et al. Hepcidin-a potential novel biomarker for iron status in chronic kidney disease. Clin J Am Soc Nephrol. 4 (2009) 1051-1056
14. Hentze M.W., Muckenthaler M.U., and Andrews N.C. Balancing acts: molecular control of mammalian iron metabolism. Cell 117 3 (2004) 285-297
15. Ganz T. Molecular control of iron transport. J Am Soc Nephrol. 18 2 (2007) 394-400
16. Andrews N.C. Forging a field: the golden age of iron biology. Blood 112 2 (2008) 219-230
17. Krause A., Neitz S., Mägert H.J., et al. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett. 480 2-3 (2000) 147-150
18. Pigeon C., Ilyin G., Courselaud B., et al. A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem. 276 11 (2001) 7811-7819
19. Park C.H., Valore E.V., Waring A.J., and Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem. 276 11 (2001) 7806-7810
20. Nemeth E., Tuttle M.S., Powelson J., et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306 5704 (2004) 2090-2093
21. Ramey G., Deschemin J.C., Durel B., Canonne-Hergaux F., Nicolas G., and Vaulont S. Hepcidin targets ferroportin for degradation in hepatocytes. Haematologica (2009) doi:10.3324/haematol.2009.014399
22. Nicolas G., Bennoun M., Devaux I., et al. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc Natl Acad Sci U S A 98 15 (2001) 8780-8785
23. Lesbordes-Brion J.C., Viatte L., Bennoun M., et al. Targeted disruption of the hepcidin 1 gene results in severe hemochromatosis. Blood 108 4 (2006) 1402-1405
24. Roetto A., Papanikolaou G., Politou M., et al. Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet. 33 1 (2003) 21-22
25. Nicolas G., Bennoun M., Porteu A., et al. Severe iron deficiency anemia in transgenic mice expressing liver hepcidin. Proc Natl Acad Sci U S A 99 7 (2002) 4596-4601
26. Weinstein D.A., Roy C.N., Fleming M.D., Loda M.F., Wolfsdorf J.I., and Andrews N.C. Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease. Blood 100 10 (2002) 3776-3781
27. Nicolas G., Chauvet C., Viatte L., et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest. 110 7 (2002) 1037-1044
28. Nemeth E., Rivera S., Gabayan V., et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 113 9 (2004) 1271-1276
29. Nemeth E., Valore E.V., Territo M., Schiller G., Lichtenstein A., and Ganz T. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood 101 7 (2003) 2461-2463
30. Pietrangelo A. Hereditary hemochromatosis. Biochim Biophys Acta. 1763 7 (2006) 700-710
31. Feder J.N., Gnirke A., Thomas W., et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet. 13 4 (1996) 399-408
32. Camaschella C., Roetto A., Calì A., et al. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet. 25 1 (2000) 14-15
33. Papanikolaou G., Samuels M.E., Ludwig E.H., et al. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet. 36 1 (2004) 77-82
34. Kawabata H., Yang R., Hirama T., et al. Molecular cloning of transferrin receptor 2. A new member of the transferrin receptor-like family. J Biol Chem. 274 30 (1999) 20826-20832
35. Bridle K.R., Frazer D.M., Wilkins S.J., et al. Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis. Lancet 361 9358 (2003) 669-673
36. Nemeth E., Roetto A., Garozzo G., Ganz T., and Camaschella C. Hepcidin is decreased in TFR2 hemochromatosis. Blood 105 4 (2005) 1803-1806
37. Huang F.W., Pinkus J.L., Pinkus G.S., Fleming M.D., and Andrews N.C. A mouse model of juvenile hemochromatosis. J Clin Invest. 115 8 (2005) 2187-2191
38. Niederkofler V., Salie R., and Arber S. Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload. J Clin Invest. 115 8 (2005) 2180-2186
39. Kawabata H., Fleming R.E., Gui D., et al. Expression of hepcidin is down-regulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis. Blood 105 1 (2005) 376-381
40. Muckenthaler M., Roy C.N., Custodio A.O., et al. Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrd1 expression in mouse hemochromatosis. Nat Genet. 34 1 (2003) 102-107
41. Nicolas G., Viatte L., Lou D.Q., et al. Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis. Nat Genet. 34 1 (2003) 97-101
42. Wallace D.F., Summerville L., Lusby P.E., and Subramaniam V.N. First phenotypic description of transferrin receptor 2 knockout mouse, and the role of hepcidin. Gut 54 7 (2005) 980-986
43. Babitt J.L., Huang F.W., Wrighting D.M., et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet. 38 5 (2006) 531-539
44. Wang R.H., Li C., Xu X., et al. A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab. 2 6 (2005) 399-409
45. Shi Y., and Massagué J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113 6 (2003) 685-700
46. Babitt J.L., Huang F.W., Xia Y., Sidis Y., Andrews N.C., and Lin H.Y. Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J Clin Invest. 117 7 (2007) 1933-1939
47. Andriopoulos Jr. B., Corradini E., Xia Y., et al. BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat Genet. 41 4 (2009) 482-487
48. Xia Y., Babitt J.L., Sidis Y., Chung R.T., and Lin H.Y. Hemojuvelin regulates hepcidin expression via a selective subset of BMP ligands and receptors independently of neogenin. Blood 111 10 (2008) 5195-5204
49. Truksa J., Peng H., Lee P., and Beutler E. Bone morphogenetic proteins 2, 4, and 9 stimulate murine hepcidin 1 expression independently of Hfe, transferrin receptor 2 (Tfr2), and IL-6. Proc Natl Acad Sci U S A 103 27 (2006) 10289-10293
50. Truksa J., Peng H., Lee P., and Beutler E. Different regulatory elements are required for response of hepcidin to interleukin-6 and bone morphogenetic proteins 4 and 9. Br J Haematol. 139 1 (2007) 138-147
51. Truksa J., Lee P., and Beutler E. Two BMP responsive elements, STAT, and bZIP/HNF4/COUP motifs of the hepcidin promoter are critical for BMP, SMAD1, and HJV responsiveness. Blood 113 3 (2009) 688-695
52. Verga Falzacappa M.V., Casanovas G., Hentze M.W., and Muckenthaler M.U. A bone morphogenetic protein (BMP)-responsive element in the hepcidin promoter controls HFE2-mediated hepatic hepcidin expression and its response to IL-6 in cultured cells. J Mol Med. 86 5 (2008) 531-540
53. Casanovas G., Mleczko-Sanecka K., Altamura S., Hentze M.W., and Muckenthaler M.U. Bone morphogenetic protein (BMP)-responsive elements located in the proximal and distal hepcidin promoter are critical for its response to HJV/BMP/SMAD. J Mol Med. 87 5 (2009) 471-480
54. Island M.L., Jouanolle A.M., Mosser A., et al. A new mutation in the hepcidin promoter impairs its BMP response and contributes to a severe phenotype in HFE related hemochromatosis. Haematologica 94 5 (2009) 720-724
55. Yu P.B., Hong C.C., Sachidanandan C., et al. Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nat Chem Biol. 4 1 (2008) 33-41
56. Meynard D., Kautz L., Darnaud V., Canonne-Hergaux F., Coppin H., and Roth M.P. Lack of the bone morphogenetic protein BMP6 induces massive iron overload. Nat Genet. 41 4 (2009) 478-481
57. Kautz L., Meynard D., Monnier A., et al. Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver. Blood 112 4 (2008) 1503-1509
58. Corradini E., Garuti C., Montosi G., et al. Bone morphogenetic protein signaling is impaired in a Hfe knockout mouse model of hemochromatosis. Gastroenterology 137 4 (2009) 1489-1497
59. Lin L., Valore E.V., Nemeth E., Goodnough J.B., Gabayan V., and Ganz T. Iron transferrin regulates hepcidin synthesis in primary hepatocyte culture through hemojuvelin and BMP2/4. Blood 110 6 (2007) 2182-2189
60. Schmidt P.J., Toran P.T., Giannetti A.M., Bjorkman P.J., and Andrews N.C. The transferrin receptor modulates Hfe-dependent regulation of hepcidin expression. Cell Metab. 7 3 (2008) 205-214
61. Gao J., Chen J., Kramer M., Tsukamoto H., Zhang A.S., and Enns C.A. Interaction of the hereditary hemochromatosis protein HFE with transferrin receptor 2 is required for transferrin-induced hepcidin expression. Cell Metab. 9 3 (2009) 217-227
62. Bennett M.J., Lebrón J.A., and Bjorkman P.J. Crystal structure of the hereditary haemochromatosis protein HFE complexed with transferrin receptor. Nature 403 6765 (2000) 46-53
63. Goswami T., and Andrews N.C. Hereditary hemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing. J Biol Chem. 281 39 (2006) 28494-28498
64. Lebrón J.A., West Jr. A.P., and Bjorkman P.J. The hemochromatosis protein HFE competes with transferrin for binding to the transferrin receptor. J Mol Biol. 294 1 (1999) 239-245
65. West Jr. A.P., Giannetti A.M., Herr A.B., et al. Mutational analysis of the transferrin receptor reveals overlapping HFE and transferrin binding sites. J Mol Biol. 313 2 (2001) 385-397
66. Giannetti A.M., and Björkman P.J. HFE and transferrin directly compete for transferrin receptor in solution and at the cell surface. J Biol Chem. 279 24 (2004) 25866-25875
67. Feder J.N., Penny D.M., Irrinki A., et al. The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Proc Natl Acad Sci U S A 95 4 (1998) 1472-1477
68. Vujić Spasić M., Kiss J., Herrmann T., et al. Hfe acts in hepatocytes to prevent hemochromatosis. Cell Metab. 7 2 (2008) 173-178
69. Wallace D.F., Summerville L., and Subramaniam V.N. Targeted disruption of the hepatic transferrin receptor 2 gene in mice leads to iron overload. Gastroenterology 132 1 (2007) 301-310
70. Pietrangelo A., Caleffi A., Henrion J., et al. Juvenile hemochromatosis associated with pathogenic mutations of adult hemochromatosis genes. Gastroenterology 128 2 (2005) 470-479
71. Wallace D.F., Summerville L., Crampton E.M., Frazer D.M., Anderson G.J., and Subramaniam V.N. Combined deletion of Hfe and transferrin receptor 2 in mice leads to marked dysregulation of hepcidin and iron overload. Hepatology 50 6 (2009) 1992-2000
72. Kautz L., Meynard D., Besson-Fournier C., et al. BMP/Smad signaling is not enhanced in Hfe-deficient mice despite increased Bmp6 expression. Blood 114 12 (2009) 2515-2520
73. Calzolari A., Raggi C., Deaglio S., et al. TfR2 localizes in lipid raft domains and is released in exosomes to activate signal transduction along the MAPK pathway. J Cell Sci. 119 pt 21 (2006) 4486-4498
74. Ramey G., Deschemin J.C., and Vaulont S. Cross-talk between the mitogen activated protein kinase and bone morphogenetic protein/hemojuvelin pathways is required for the induction of hepcidin by holotransferrin in primary mouse hepatocytes. Haematologica 94 6 (2009) 765-772
75. Wrighting D.M., and Andrews N.C. Interleukin-6 induces hepcidin expression through STAT3. Blood 108 9 (2006) 3204-3209
76. Verga Falzacappa M.V., Vujic Spasic M., Kessler R., Stolte J., Hentze M.W., and Muckenthaler M.U. STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation. Blood 109 1 (2007) 353-358
77. Pietrangelo A., Dierssen U., Valli L., et al. STAT3 is required for IL-6-gp130-dependent activation of hepcidin in vivo. Gastroenterology 132 1 (2007) 294-300
78. Lee P., Peng H., Gelbart T., Wang L., and Beutler E. Regulation of hepcidin transcription by interleukin-1 and interleukin-6. Proc Natl Acad Sci U S A 102 6 (2005) 1906-1910
79. Zhang K., Shen X., Wu J., et al. Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response. Cell 124 3 (2006) 587-599
80. Vecchi C., Montosi G., Zhang K., et al. ER stress controls iron metabolism through induction of hepcidin. Science 325 5942 (2009) 877-880
81. Oliveira S.J., Pinto J.P., Picarote G., et al. ER stress-inducible factor CHOP affects the expression of hepcidin by modulating C/EBPalpha activity. PLoS One 4 8 (2009) e6618
82. Liu X.B., Nguyen N.B., Marquess K.D., Yang F., and Haile D.J. Regulation of hepcidin and ferroportin expression by lipopolysaccharide in splenic macrophages. Blood Cells Mol Dis. 35 1 (2005) 47-56
83. Peyssonnaux C., Zinkernagel A.S., Datta V., Lauth X., Johnson R.S., and Nizet V. TLR4-dependent hepcidin expression by myeloid cells in response to bacterial pathogens. Blood 107 9 (2006) 3727-3732
84. Sow F.B., Florence W.C., Satoskar A.R., et al. Expression and localization of hepcidin in macrophages: a role in host defense against tuberculosis. J Leukoc Biol. 82 4 (2007) 934-945
85. Koening C.L., Miller J.C., Nelson J.M., et al. Toll-like receptors mediate induction of hepcidin in mice infected with Borrelia burgdorferi. Blood 114 9 (2009) 1913-1918
86. Theurl I., Theurl M., Seifert M., et al. Autocrine formation of hepcidin induces iron retention in human monocytes. Blood 111 4 (2008) 2392-2399
87. Lin L., Goldberg Y.P., and Ganz T. Competitive regulation of hepcidin mRNA by soluble and cell-associated hemojuvelin. Blood 106 8 (2005) 2884-2889
88. Kuninger D., Kuns-Hashimoto R., Kuzmickas R., and Rotwein P. Complex biosynthesis of the muscle-enriched iron regulator RGMc. J Cell Sci. 119 pt 16 (2006) 3273-3283
89. Zhang A.S., Anderson S.A., Meyers K.R., Hernandez C., Eisenstein R.S., and Enns C.A. Evidence that inhibition of hemojuvelin shedding in response to iron is mediated through neogenin. J Biol Chem. 282 17 (2007) 12547-12556
90. Silvestri L., Pagani A., Fazi C., et al. Defective targeting of hemojuvelin to plasma membrane is a common pathogenetic mechanism in juvenile hemochromatosis. Blood 109 10 (2007) 4503-4510
91. Kuninger D., Kuns-Hashimoto R., Nili M., and Rotwein P. Pro-protein convertases control the maturation and processing of the iron-regulatory protein, RGMc/hemojuvelin. BMC Biochem. 9 (2008) 9
92. Silvestri L., Pagani A., and Camaschella C. Furin-mediated release of soluble hemojuvelin: a new link between hypoxia and iron homeostasis. Blood 111 2 (2008) 924-931
93. Lin L., Nemeth E., Goodnough J.B., Thapa D.R., Gabayan V., and Ganz T. Soluble hemojuvelin is released by proprotein convertase-mediated cleavage at a conserved polybasic RNRR site. Blood Cells Mol Dis. 40 1 (2008) 122-131
94. Silvestri L., Pagani A., Nai A., De Domenico I., Kaplan J., and Camaschella C. The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. Cell Metab. 8 6 (2008) 502-511
95. Zhang A.S., West Jr. A.P., Wyman A.E., Bjorkman P.J., and Enns C.A. Interaction of hemojuvelin with neogenin results in iron accumulation in human embryonic kidney 293 cells. J Biol Chem. 280 40 (2005) 33885-33894
96. Nicolas G., Viatte L., Bennoun M., Beaumont C., Kahn A., and Vaulont S. Hepcidin, a new iron regulatory peptide. Blood Cells Mol Dis. 29 3 (2002) 327-335
97. Kearney S.L., Nemeth E., Neufeld E.J., et al. Urinary hepcidin in congenital chronic anemias. Pediatr Blood Cancer 48 1 (2007) 57-63
98. Origa R., Galanello R., Ganz T., et al. Liver iron concentrations and urinary hepcidin in beta-thalassemia. Haematologica 92 5 (2007) 583-588
99. Pinto J.P., Ribeiro S., Pontes H., et al. Erythropoietin mediates hepcidin expression in hepatocytes through EPOR signaling and regulation of C/EBPalpha. Blood 111 12 (2008) 5727-5733
100. Pak M., Lopez M.A., Gabayan V., Ganz T., and Rivera S. Suppression of hepcidin during anemia requires erythropoietic activity. Blood 108 12 (2006) 3730-3735
101. Vokurka M., Krijt J., Sulc K., and Necas E. Hepcidin mRNA levels in mouse liver respond to inhibition of erythropoiesis. Physiol Res. 55 6 (2006) 667-674
102. Tanno T., Bhanu N.V., Oneal P.A., et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med. 13 9 (2007) 1096-1101
103. Tanno T., Porayette P., Sripichai O., et al. Identification of TWSG1 as a second novel erythroid regulator of hepcidin expression in murine and human cells. Blood 114 1 (2009) 181-186
104. Oelgeschläger M., Larraín J., Geissert D., and De Robertis E.M. The evolutionarily conserved BMP-binding protein Twisted gastrulation promotes BMP signalling. Nature 405 6788 (2000) 757-763
105. Ross J.J., Shimmi O., Vilmos P., et al. Twisted gastrulation is a conserved extracellular BMP antagonist. Nature 410 6827 (2001) 479-483
106. Chang C., Holtzman D.A., Chau S., et al. Twisted gastrulation can function as a BMP antagonist. Nature 410 6827 (2001) 483-487
107. Xu J., Kimball T.R., Lorenz J.N., et al. GDF15/MIC-1 functions as a protective and antihypertrophic factor released from the myocardium in association with SMAD protein activation. Circ Res. 98 3 (2006) 342-350
108. Hsiao E.C., Koniaris L.G., Zimmers-Koniaris T., Sebald S.M., Huynh T.V., and Lee S.J. Characterization of growth-differentiation factor 15, a transforming growth factor beta superfamily member induced following liver injury. Mol Cell Biol. 20 10 (2000) 3742-3751
109. Eling T.E., Baek S.J., Shim M., and Lee C.H. NSAID activated gene (NAG-1), a modulator of tumorigenesis. J Biochem Mol Biol. 39 6 (2006) 649-655
110. Peyssonnaux C., Nizet V., and Johnson R.S. Role of the hypoxia inducible factors HIF in iron metabolism. Cell Cycle 7 1 (2008) 28-32
111. Peyssonnaux C., Zinkernagel A.S., Schuepbach R.A., et al. Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J Clin Invest. 117 7 (2007) 1926-1932
112. Choi S.O., Cho Y.S., Kim H.L., and Park J.W. ROS mediate the hypoxic repression of the hepcidin gene by inhibiting C/EBPalpha and STAT-3. Biochem Biophys Res Commun. 356 1 (2007) 312-317
113. Braliou G.G., Verga Falzacappa M.V., Chachami G., Casanovas G., Muckenthaler M.U., and Simos G. 2-Oxoglutarate-dependent oxygenases control hepcidin gene expression. J Hepatol. 48 5 (2008) 801-810
114. Lok C.N., and Ponka P. Identification of a hypoxia response element in the transferrin receptor gene. J Biol Chem. 274 34 (1999) 24147-24152
115. Tacchini L., Bianchi L., Bernelli-Zazzera A., and Cairo G. Transferrin receptor induction by hypoxia. HIF-1-mediated transcriptional activation and cell-specific post-transcriptional regulation. J Biol Chem. 274 34 (1999) 24142-24146
116. Mole D.R. Iron homeostasis and its interaction with prolyl hydroxylases. Antioxid Redox Signal 12 4 (2010) 445-458
117. Shah Y.M., Matsubara T., Ito S., Yim S.H., and Gonzalez F.J. Intestinal hypoxia-inducible transcription factors are essential for iron absorption following iron deficiency. Cell Metab. 9 2 (2009) 152-164
118. Mastrogiannaki M., Matak P., Keith B., Simon M.C., Vaulont S., and Peyssonnaux C. HIF-2alpha, but not HIF-1alpha, promotes iron absorption in mice. J Clin Invest. 119 5 (2009) 1159-1166
119. Du X., She E., Gelbart T., et al. The serine protease TMPRSS6 is required to sense iron deficiency. Science 320 5879 (2008) 1088-1092
120. Finberg K.E., Heeney M.M., Campagna D.R., et al. Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat Genet. 40 5 (2008) 569-571
121. Folgueras A.R., de Lara F.M., Pendás A.M., et al. Membrane-bound serine protease matriptase-2 (Tmprss6) is an essential regulator of iron homeostasis. Blood 112 6 (2008) 2539-2545
122. Velasco G., Cal S., Quesada V., Sánchez L.M., and López-Otín C. Matriptase-2, a membrane-bound mosaic serine proteinase predominantly expressed in human liver and showing degrading activity against extracellular matrix proteins. J Biol Chem. 277 40 (2002) 37637-37646
123. Truksa J., Gelbart T., Peng H., Beutler E., Beutler B., and Lee P. Suppression of the hepcidin-encoding gene Hamp permits iron overload in mice lacking both hemojuvelin and matriptase-2/TMPRSS6. Br J Haematol. 147 4 (2009) 571-581
124. Lakhal S., Talbot N.P., Crosby A., et al. Regulation of growth differentiation factor 15 expression by intracellular iron. Blood 113 7 (2009) 1555-1563
125. Valore E.V., and Ganz T. Posttranslational processing of hepcidin in human hepatocytes is mediated by the prohormone convertase furin. Blood Cells Mol Dis. 40 1 (2008) 132-138
126. Hunter H.N., Fulton D.B., Ganz T., and Vogel H.J. The solution structure of human hepcidin, a peptide hormone with antimicrobial activity that is involved in iron uptake and hereditary hemochromatosis. J Biol Chem. 277 40 (2002) 37597-37603
127. Jordan J.B., Poppe L., Haniu M., et al. Hepcidin revisited, disulfide connectivity, dynamics, and structure. J Biol Chem. 284 36 (2009) 24155-24167
128. Kemna E.H., Tjalsma H., Podust V.N., and Swinkels D.W. Mass spectrometry-based hepcidin measurements in serum and urine: analytical aspects and clinical implications. Clin Chem. 53 4 (2007) 620-628
129. Schranz M., Bakry R., Creus M., Bonn G., Vogel W., and Zoller H. Activation and inactivation of the iron hormone hepcidin: biochemical characterization of prohepcidin cleavage and sequential degradation to N-terminally truncated hepcidin isoforms. Blood Cells Mol Dis. 43 2 (2009) 169-179
130. Nemeth E., Preza G.C., Jung C.L., Kaplan J., Waring A.J., and Ganz T. The N-terminus of hepcidin is essential for its interaction with ferroportin: structure-function study. Blood 107 1 (2006) 328-333
131. Rivera S., Nemeth E., Gabayan V., Lopez M.A., Farshidi D., and Ganz T. Synthetic hepcidin causes rapid dose-dependent hypoferremia and is concentrated in ferroportin-containing organs. Blood 106 6 (2005) 2196-2199
132. Gagliardo B., Kubat N., Faye A., et al. Pro-hepcidin is unable to degrade the iron exporter ferroportin unless maturated by a furin-dependent process. J Hepatol. 50 2 (2009) 394-401
133. Swinkels D.W., Girelli D., Laarakkers C., et al. Advances in quantitative hepcidin measurements by time-of-flight mass spectrometry. PLoS One 3 7 (2008) e2706
134. Peslova G., Petrak J., Kuzelova K., et al. Hepcidin, the hormone of iron metabolism, is bound specifically to alpha-2-macroglobulin in blood. Blood 113 24 (2009) 6225-6236
135. Roe M.A., Spinks C., Heath A.L., et al. Serum prohepcidin concentration: no association with iron absorption in healthy men; and no relationship with iron status in men carrying HFE mutations, hereditary haemochromatosis patients undergoing phlebotomy treatment, or pregnant women. Br J Nutr. 97 3 (2007) 544-549
136. Kemna E., Pickkers P., Nemeth E., van der Hoeven H., and Swinkels D. Time-course analysis of hepcidin, serum iron, and plasma cytokine levels in humans injected with LPS. Blood 106 5 (2005) 1864-1866
137. Tomosugi N., Kawabata H., Wakatabe R., et al. Detection of serum hepcidin in renal failure and inflammation by using ProteinChip System. Blood 108 4 (2006) 1381-1387
138. Kemna E., Tjalsma H., Laarakkers C., Nemeth E., Willems H., and Swinkels D. Novel urine hepcidin assay by mass spectrometry. Blood 106 9 (2005) 3268-3270
139. Murphy A.T., Witcher D.R., Luan P., and Wroblewski V.J. Quantitation of hepcidin from human and mouse serum using liquid chromatography tandem mass spectrometry. Blood 110 3 (2007) 1048-1054
140. Murao N., Ishigai M., Yasuno H., Shimonaka Y., and Aso Y. Simple and sensitive quantification of bioactive peptides in biological matrices using liquid chromatography/selected reaction monitoring mass spectrometry coupled with trichloroacetic acid clean-up. Rapid Commun Mass Spectrom. 21 24 (2007) 4033-4038
141. Kobold U., Dülffer T., Dangl M., et al. Quantification of hepcidin-25 in human serum by isotope dilution micro-HPLC-tandem mass spectrometry. Clin Chem. 54 9 (2008) 1584-1586
142. De Domenico I., Nemeth E., Nelson J.M., et al. The hepcidin-binding site on ferroportin is evolutionarily conserved. Cell Metab. 8 2 (2008) 146-156
143. Grebenchtchikov N., Geurts-Moespot A.J., Kroot J.J., et al. High-sensitive radioimmunoassay for human serum hepcidin. Br J Haematol. 146 3 (2009) 317-325
144. Koliaraki V., Marinou M., Vassilakopoulos T.P., et al. A novel immunological assay for hepcidin quantification in human serum. PLoS One 4 2 (2009) e4581
145. Kroot J.J., Kemna E.H., Bansal S.S., et al. Results of the first international round robin for the quantification of urinary and plasma hepcidin assays: need for standardization. Haematologica 94 12 (2009) 1748-1752
146. Weiss G., Theurl I., Eder S., et al. Serum hepcidin concentration in chronic haemodialysis patients: associations and effects of dialysis, iron and erythropoietin therapy. Eur J Clin Invest. 39 10 (2009) 883-890
147. Peters H.P., Laarakkers C.M., Swinkels D.W., and Wetzels J.F. Serum hepcidin-25 levels in patients with chronic kidney disease are independent of glomerular filtration rate. Nephrol Dial Transplant. (2009) doi:10.1093/ndt/gfp546
148. Kato A., Tsuji T., Luo J., Sakao Y., Yasuda H., and Hishida A. Association of prohepcidin and hepcidin-25 with erythropoietin response and ferritin in hemodialysis patients. Am J Nephrol. 28 1 (2008) 115-121
149. Swinkels D.W., and Wetzels J.F. Hepcidin: a new tool in the management of anaemia in patients with chronic kidney disease?. Nephrol Dial Transplant. 23 8 (2008) 2450-2453