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American Journal of Kidney Diseases
Volume 55, Issue 4
, Pages 726-741
, April 2010
Molecular Mechanisms of Hepcidin Regulation: Implications for the Anemia of CKD
References
- . KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis. 2006;47(5 suppl 3):S1–S145
- 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. 1998;339(9):584–590
- Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355(20):2085–2098
- Secondary analysis of the CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes. Kidney Int. 2008;74(6):791–798
- . Anemia of chronic disease. N Engl J Med. 2005;352(10):1011–1023
- . Hepcidin in anemia and inflammation in chronic kidney disease. Kidney Blood Press Res. 2007;30(1):15–30
- . A randomized controlled study of iron supplementation in patients treated with erythropoietin. Kidney Int. 1996;50(5):1694–1699
- . Correction of uremic iron deficiency anemia in hemodialyzed patients: a prospective study. Nephron. 1998;79(3):299–305
- . An evaluation of the effectiveness of oral iron therapy in hemodialysis patients receiving recombinant human erythropoietin. Clin Nephrol. 1997;48(1):34–40
- . Disturbances of acquired immunity in hemodialysis patients. Semin Dial. 2007;20(5):440–451
- . Immunoassay for human serum hepcidin. Blood. 2008;112:4292–4297
- Plasma hepcidin levels are elevated but responsive to erythropoietin therapy in renal disease. Kidney Int. 2009;75(9):976–981
- Hepcidin—a potential novel biomarker for iron status in chronic kidney disease. Clin J Am Soc Nephrol. 2009;4:1051–1056
- . Balancing acts: molecular control of mammalian iron metabolism. Cell. 2004;117(3):285–297
- . Molecular control of iron transport. J Am Soc Nephrol. 2007;18(2):394–400
- . Forging a field: the golden age of iron biology. Blood. 2008;112(2):219–230
- LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett. 2000;480(2-3):147–150
- A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem. 2001;276(11):7811–7819
- . Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem. 2001;276(11):7806–7810
- Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306(5704):2090–2093
- . Hepcidin targets ferroportin for degradation in hepatocytes. Haematologica. 2009;doi:10.3324/haematol.2009.014399
- 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. 2001;98(15):8780–8785
- Targeted disruption of the hepcidin 1 gene results in severe hemochromatosis. Blood. 2006;108(4):1402–1405
- Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet. 2003;33(1):21–22
- Severe iron deficiency anemia in transgenic mice expressing liver hepcidin. Proc Natl Acad Sci U S A. 2002;99(7):4596–4601
- . Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease. Blood. 2002;100(10):3776–3781
- The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest. 2002;110(7):1037–1044
- IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 2004;113(9):1271–1276
- . Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood. 2003;101(7):2461–2463
- . Hereditary hemochromatosis. Biochim Biophys Acta. 2006;1763(7):700–710
- A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet. 1996;13(4):399–408
- The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet. 2000;25(1):14–15
- Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet. 2004;36(1):77–82
- Molecular cloning of transferrin receptor 2 (A new member of the transferrin receptor-like family). J Biol Chem. 1999;274(30):20826–20832
- Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis. Lancet. 2003;361(9358):669–673
- . Hepcidin is decreased in TFR2 hemochromatosis. Blood. 2005;105(4):1803–1806
- . A mouse model of juvenile hemochromatosis. J Clin Invest. 2005;115(8):2187–2191
- . Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload. J Clin Invest. 2005;115(8):2180–2186
- Expression of hepcidin is down-regulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis. Blood. 2005;105(1):376–381
- Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrd1 expression in mouse hemochromatosis. Nat Genet. 2003;34(1):102–107
- Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis. Nat Genet. 2003;34(1):97–101
- . First phenotypic description of transferrin receptor 2 knockout mouse, and the role of hepcidin. Gut. 2005;54(7):980–986
- Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet. 2006;38(5):531–539
- A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab. 2005;2(6):399–409
- . Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 2003;113(6):685–700
- . Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J Clin Invest. 2007;117(7):1933–1939
- BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat Genet. 2009;41(4):482–487
- . Hemojuvelin regulates hepcidin expression via a selective subset of BMP ligands and receptors independently of neogenin. Blood. 2008;111(10):5195–5204
- . 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. 2006;103(27):10289–10293
- . Different regulatory elements are required for response of hepcidin to interleukin-6 and bone morphogenetic proteins 4 and 9. Br J Haematol. 2007;139(1):138–147
- . Two BMP responsive elements, STAT, and bZIP/HNF4/COUP motifs of the hepcidin promoter are critical for BMP, SMAD1, and HJV responsiveness. Blood. 2009;113(3):688–695
- . 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. 2008;86(5):531–540
- . 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. 2009;87(5):471–480
- A new mutation in the hepcidin promoter impairs its BMP response and contributes to a severe phenotype in HFE related hemochromatosis. Haematologica. 2009;94(5):720–724
- Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nat Chem Biol. 2008;4(1):33–41
- . Lack of the bone morphogenetic protein BMP6 induces massive iron overload. Nat Genet. 2009;41(4):478–481
- Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver. Blood. 2008;112(4):1503–1509
- Bone morphogenetic protein signaling is impaired in a Hfe knockout mouse model of hemochromatosis. Gastroenterology. 2009;137(4):1489–1497
- . Iron transferrin regulates hepcidin synthesis in primary hepatocyte culture through hemojuvelin and BMP2/4. Blood. 2007;110(6):2182–2189
- . The transferrin receptor modulates Hfe-dependent regulation of hepcidin expression. Cell Metab. 2008;7(3):205–214
- . Interaction of the hereditary hemochromatosis protein HFE with transferrin receptor 2 is required for transferrin-induced hepcidin expression. Cell Metab. 2009;9(3):217–227
- . Crystal structure of the hereditary haemochromatosis protein HFE complexed with transferrin receptor. Nature. 2000;403(6765):46–53
- . Hereditary hemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing. J Biol Chem. 2006;281(39):28494–28498
- . The hemochromatosis protein HFE competes with transferrin for binding to the transferrin receptor. J Mol Biol. 1999;294(1):239–245
- Mutational analysis of the transferrin receptor reveals overlapping HFE and transferrin binding sites. J Mol Biol. 2001;313(2):385–397
- . HFE and transferrin directly compete for transferrin receptor in solution and at the cell surface. J Biol Chem. 2004;279(24):25866–25875
- The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Proc Natl Acad Sci U S A. 1998;95(4):1472–1477
- Hfe acts in hepatocytes to prevent hemochromatosis. Cell Metab. 2008;7(2):173–178
- . Targeted disruption of the hepatic transferrin receptor 2 gene in mice leads to iron overload. Gastroenterology. 2007;132(1):301–310
- Juvenile hemochromatosis associated with pathogenic mutations of adult hemochromatosis genes. Gastroenterology. 2005;128(2):470–479
- . Combined deletion of Hfe and transferrin receptor 2 in mice leads to marked dysregulation of hepcidin and iron overload. Hepatology. 2009;50(6):1992–2000
- BMP/Smad signaling is not enhanced in Hfe-deficient mice despite increased Bmp6 expression. Blood. 2009;114(12):2515–2520
- TfR2 localizes in lipid raft domains and is released in exosomes to activate signal transduction along the MAPK pathway. J Cell Sci. 2006;119(pt 21):4486–4498
- . 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. 2009;94(6):765–772
- . Interleukin-6 induces hepcidin expression through STAT3. Blood. 2006;108(9):3204–3209
- . STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation. Blood. 2007;109(1):353–358
- STAT3 is required for IL-6-gp130-dependent activation of hepcidin in vivo. Gastroenterology. 2007;132(1):294–300
- . Regulation of hepcidin transcription by interleukin-1 and interleukin-6. Proc Natl Acad Sci U S A. 2005;102(6):1906–1910
- Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response. Cell. 2006;124(3):587–599
- ER stress controls iron metabolism through induction of hepcidin. Science. 2009;325(5942):877–880
- ER stress-inducible factor CHOP affects the expression of hepcidin by modulating C/EBPalpha activity. PLoS One. 2009;4(8):e6618
- . Regulation of hepcidin and ferroportin expression by lipopolysaccharide in splenic macrophages. Blood Cells Mol Dis. 2005;35(1):47–56
- . TLR4-dependent hepcidin expression by myeloid cells in response to bacterial pathogens. Blood. 2006;107(9):3727–3732
- Expression and localization of hepcidin in macrophages: a role in host defense against tuberculosis. J Leukoc Biol. 2007;82(4):934–945
- Toll-like receptors mediate induction of hepcidin in mice infected with Borrelia burgdorferi. Blood. 2009;114(9):1913–1918
- Autocrine formation of hepcidin induces iron retention in human monocytes. Blood. 2008;111(4):2392–2399
- . Competitive regulation of hepcidin mRNA by soluble and cell-associated hemojuvelin. Blood. 2005;106(8):2884–2889
- . Complex biosynthesis of the muscle-enriched iron regulator RGMc. J Cell Sci. 2006;119(pt 16):3273–3283
- . Evidence that inhibition of hemojuvelin shedding in response to iron is mediated through neogenin. J Biol Chem. 2007;282(17):12547–12556
- Defective targeting of hemojuvelin to plasma membrane is a common pathogenetic mechanism in juvenile hemochromatosis. Blood. 2007;109(10):4503–4510
- . Pro-protein convertases control the maturation and processing of the iron-regulatory protein, RGMc/hemojuvelin. BMC Biochem. 2008;9:9
- . Furin-mediated release of soluble hemojuvelin: a new link between hypoxia and iron homeostasis. Blood. 2008;111(2):924–931
- . Soluble hemojuvelin is released by proprotein convertase-mediated cleavage at a conserved polybasic RNRR site. Blood Cells Mol Dis. 2008;40(1):122–131
- . The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. Cell Metab. 2008;8(6):502–511
- . Interaction of hemojuvelin with neogenin results in iron accumulation in human embryonic kidney 293 cells. J Biol Chem. 2005;280(40):33885–33894
- . Hepcidin, a new iron regulatory peptide. Blood Cells Mol Dis. 2002;29(3):327–335
- Urinary hepcidin in congenital chronic anemias. Pediatr Blood Cancer. 2007;48(1):57–63
- Liver iron concentrations and urinary hepcidin in beta-thalassemia. Haematologica. 2007;92(5):583–588
- Erythropoietin mediates hepcidin expression in hepatocytes through EPOR signaling and regulation of C/EBPalpha. Blood. 2008;111(12):5727–5733
- . Suppression of hepcidin during anemia requires erythropoietic activity. Blood. 2006;108(12):3730–3735
- . Hepcidin mRNA levels in mouse liver respond to inhibition of erythropoiesis. Physiol Res. 2006;55(6):667–674
- High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med. 2007;13(9):1096–1101
- Identification of TWSG1 as a second novel erythroid regulator of hepcidin expression in murine and human cells. Blood. 2009;114(1):181–186
- . The evolutionarily conserved BMP-binding protein Twisted gastrulation promotes BMP signalling. Nature. 2000;405(6788):757–763
- Twisted gastrulation is a conserved extracellular BMP antagonist. Nature. 2001;410(6827):479–483
- Twisted gastrulation can function as a BMP antagonist. Nature. 2001;410(6827):483–487
- GDF15/MIC-1 functions as a protective and antihypertrophic factor released from the myocardium in association with SMAD protein activation. Circ Res. 2006;98(3):342–350
- . Characterization of growth-differentiation factor 15, a transforming growth factor beta superfamily member induced following liver injury. Mol Cell Biol. 2000;20(10):3742–3751
- . NSAID activated gene (NAG-1), a modulator of tumorigenesis. J Biochem Mol Biol. 2006;39(6):649–655
- . Role of the hypoxia inducible factors HIF in iron metabolism. Cell Cycle. 2008;7(1):28–32
- Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J Clin Invest. 2007;117(7):1926–1932
- . ROS mediate the hypoxic repression of the hepcidin gene by inhibiting C/EBPalpha and STAT-3. Biochem Biophys Res Commun. 2007;356(1):312–317
- . 2-Oxoglutarate-dependent oxygenases control hepcidin gene expression. J Hepatol. 2008;48(5):801–810
- . Identification of a hypoxia response element in the transferrin receptor gene. J Biol Chem. 1999;274(34):24147–24152
- . Transferrin receptor induction by hypoxia (HIF-1-mediated transcriptional activation and cell-specific post-transcriptional regulation). J Biol Chem. 1999;274(34):24142–24146
- . Iron homeostasis and its interaction with prolyl hydroxylases. Antioxid Redox Signal. 2010;12(4):445–458
- . Intestinal hypoxia-inducible transcription factors are essential for iron absorption following iron deficiency. Cell Metab. 2009;9(2):152–164
- . HIF-2alpha, but not HIF-1alpha, promotes iron absorption in mice. J Clin Invest. 2009;119(5):1159–1166
- The serine protease TMPRSS6 is required to sense iron deficiency. Science. 2008;320(5879):1088–1092
- Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat Genet. 2008;40(5):569–571
- Membrane-bound serine protease matriptase-2 (Tmprss6) is an essential regulator of iron homeostasis. Blood. 2008;112(6):2539–2545
- . Matriptase-2, a membrane-bound mosaic serine proteinase predominantly expressed in human liver and showing degrading activity against extracellular matrix proteins. J Biol Chem. 2002;277(40):37637–37646
- . Suppression of the hepcidin-encoding gene Hamp permits iron overload in mice lacking both hemojuvelin and matriptase-2/TMPRSS6. Br J Haematol. 2009;147(4):571–581
- Regulation of growth differentiation factor 15 expression by intracellular iron. Blood. 2009;113(7):1555–1563
- . Posttranslational processing of hepcidin in human hepatocytes is mediated by the prohormone convertase furin. Blood Cells Mol Dis. 2008;40(1):132–138
- . The solution structure of human hepcidin, a peptide hormone with antimicrobial activity that is involved in iron uptake and hereditary hemochromatosis. J Biol Chem. 2002;277(40):37597–37603
- Hepcidin revisited, disulfide connectivity, dynamics, and structure. J Biol Chem. 2009;284(36):24155–24167
- . Mass spectrometry-based hepcidin measurements in serum and urine: analytical aspects and clinical implications. Clin Chem. 2007;53(4):620–628
- . 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. 2009;43(2):169–179
- . The N-terminus of hepcidin is essential for its interaction with ferroportin: structure-function study. Blood. 2006;107(1):328–333
- . Synthetic hepcidin causes rapid dose-dependent hypoferremia and is concentrated in ferroportin-containing organs. Blood. 2005;106(6):2196–2199
- Pro-hepcidin is unable to degrade the iron exporter ferroportin unless maturated by a furin-dependent process. J Hepatol. 2009;50(2):394–401
- Advances in quantitative hepcidin measurements by time-of-flight mass spectrometry. PLoS One. 2008;3(7):e2706
- Hepcidin, the hormone of iron metabolism, is bound specifically to alpha-2-macroglobulin in blood. Blood. 2009;113(24):6225–6236
- 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. 2007;97(3):544–549
- . Time-course analysis of hepcidin, serum iron, and plasma cytokine levels in humans injected with LPS. Blood. 2005;106(5):1864–1866
- Detection of serum hepcidin in renal failure and inflammation by using ProteinChip System. Blood. 2006;108(4):1381–1387
- . Novel urine hepcidin assay by mass spectrometry. Blood. 2005;106(9):3268–3270
- . Quantitation of hepcidin from human and mouse serum using liquid chromatography tandem mass spectrometry. Blood. 2007;110(3):1048–1054
- . 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. 2007;21(24):4033–4038
- Quantification of hepcidin-25 in human serum by isotope dilution micro-HPLC-tandem mass spectrometry. Clin Chem. 2008;54(9):1584–1586
- The hepcidin-binding site on ferroportin is evolutionarily conserved. Cell Metab. 2008;8(2):146–156
- High-sensitive radioimmunoassay for human serum hepcidin. Br J Haematol. 2009;146(3):317–325
- A novel immunological assay for hepcidin quantification in human serum. PLoS One. 2009;4(2):e4581
- Results of the first international round robin for the quantification of urinary and plasma hepcidin assays: need for standardization. Haematologica. 2009;94(12):1748–1752
- Serum hepcidin concentration in chronic haemodialysis patients: associations and effects of dialysis, iron and erythropoietin therapy. Eur J Clin Invest. 2009;39(10):883–890
- . 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
- . Association of prohepcidin and hepcidin-25 with erythropoietin response and ferritin in hemodialysis patients. Am J Nephrol. 2008;28(1):115–121
- . Hepcidin: a new tool in the management of anaemia in patients with chronic kidney disease?. Nephrol Dial Transplant. 2008;23(8):2450–2453
Originally published online as doi:10.1053/j.ajkd.2009.12.030 on March 2, 2010.
PII: S0272-6386(10)00029-6
doi: 10.1053/j.ajkd.2009.12.030
© 2010 National Kidney Foundation, Inc. Published by Elsevier Inc All rights reserved.
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American Journal of Kidney Diseases
Volume 55, Issue 4
, Pages 726-741
, April 2010
