Hypoxic regulation of erythropoiesis and iron metabolism

American Journal of Physiology - Renal Physiology

Volumn 299, Issue 1, 2010, Pages

  Haase, Volker H ^a  

^a VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Erythropoietin; Hypoxia; Hypoxia inducible factors; Iron; Red blood cells

Indexed keywords

ERYTHROPOIETIN; HYPOXIA INDUCIBLE FACTOR; OXYGEN; RECOMBINANT ERYTHROPOIETIN; TRANSCRIPTION FACTOR;

ANEMIA; BONE MARROW; ERYTHROCYTOSIS; ERYTHROPOIESIS; GENE CONTROL; HOMEOSTASIS; HUMAN; HYDROXYLATION; HYPOXIA; IRON METABOLISM; NONHUMAN; PRIORITY JOURNAL; PROTEIN PROCESSING; PROTEIN SYNTHESIS; REVIEW;

EID: 77953854244     PISSN: 1931857X     EISSN: 15221466     Source Type: Journal    
DOI: 10.1152/ajprenal.00174.2010     Document Type: Review

References (170)

1. Adelman DM, Maltepe E, Simon MC. Multilineage embryonic hematopoiesis requires hypoxic ARNT activity. Genes Dev 13: 2478-2483, 1999. (Pubitemid 29489639)
2. An WG, Kanekal M, Simon MC, Maltepe E, Blagosklonny MV, Neckers LM. Stabilization of wild-type p53 by hypoxia-inducible factor 1alpha. Nature 392: 405-408, 1998.
3. Andrews NC. Forging a field: the golden age of iron biology. Blood 112: 219-230, 2008.
4. Andriopoulos B Jr, Corradini E, Xia Y, Faasse SA, Chen S, Grgurevic L, Knutson MD, Pietrangelo A, Vukicevic S, Lin HY, Babitt JL. BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat Genet 41: 482-487, 2009.
5. Ang SO, Chen H, Hirota K, Gordeuk VR, Jelinek J, Guan Y, Liu E, Sergueeva AI, Miasnikova GY, Mole D, Maxwell PH, Stockton DW, Semenza GL, Prchal JT. Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. Nat Genet 32: 614-621, 2002.
6. Appelhoff RJ, Tian YM, Raval RR, Turley H, Harris AL, Pugh CW, Ratcliffe PJ, Gleadle JM. Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. J Biol Chem 279: 38458-38465, 2004. (Pubitemid 39295997)
7. Aprelikova O, Wood M, Tackett S, Chandramouli GV, Barrett JC. Role of ETS transcription factors in the hypoxia-inducible factor-2 target gene selection. Cancer Res 66: 5641-5647, 2006. (Pubitemid 43927116)
8. Babitt JL, Huang FW, Wrighting DM, Xia Y, Sidis Y, Samad TA, Campagna JA, Chung RT, Schneyer AL, Woolf CJ, Andrews NC, Lin HY. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet 38: 531-539, 2006.
9. Bachmann S, Le Hir M, Eckardt KU. Co-localization of erythropoietin mRNA and ecto-5′-nucleotidase immunoreactivity in peritubular cells of rat renal cortex indicates that fibroblasts produce erythropoietin. J Histochem Cytochem 41: 335-341, 1993. (Pubitemid 23061919)
10. Bernaudin M, Bellail A, Marti HH, Yvon A, Vivien D, Duchatelle I, Mackenzie ET, Petit E. Neurons and astrocytes express EPO mRNA: oxygen-sensing mechanisms that involve the redox-state of the brain. Glia 30: 271-278, 2000. (Pubitemid 30259666)
11. Bernhardt W, Wiesener M, Schmieder R, Guenzler V, Eckardt KU. The prolylhydroxyalse inhibitor FG2216 stimulates EPO production in nephric and anephric dialysis patients: evidence for an underutilized production capacity in liver and kidneys. ASN Annual Meeting, San Francisco CA. J Am Soc Nephrol 18: SA-PO784, 2007.
12. Bert P. La Pression Barométrique: Recherches de Physiologie Expérimentale. Paris: Masson, 1878.
13. Bert P. Sur la richesse en hemoglobine du sang des animaux vivant sur les hauts lieux. C R Acad Sci Paris 94: 805-807, 1882.
14. Besarab A, Frinak S, Yee J. What is so bad about a hemoglobin level of 12 to 13 g/dL for chronic kidney disease patients anyway? Adv Chronic Kidney Dis 16: 131-142, 2009.
15. Blanchard KL, Acquaviva AM, Galson DL, Bunn HF. Hypoxic induction of the human erythropoietin gene: cooperation between the promoter and enhancer, each of which contains steroid receptor response elements. Mol Cell Biol 12: 5373-5385, 1992.
16. Bodo E, Kromminga A, Funk W, Laugsch M, Duske U, Jelkmann W, Paus R. Human hair follicles are an extrarenal source and a nonhematopoietic target of erythropoietin. FASEB J 21: 3346-3354, 2007. (Pubitemid 47565553)
17. Boutin AT, Weidemann A, Fu Z, Mesropian L, Gradin K, Jamora C, Wiesener M, Eckardt KU, Koch CJ, Ellies LG, Haddad G, Haase VH, Simon MC, Poellinger L, Powell FL, Johnson RS. Epidermal sensing of oxygen is essential for systemic hypoxic response. Cell 133: 223-234, 2008.
18. Braliou GG, Verga Falzacappa MV, Chachami G, Casanovas G, Muckenthaler MU, Simos G. 2-Oxoglutarate-dependent oxygenases control hepcidin gene expression. J Hepatol 48: 801-810, 2008.
19. Bruick RK. Oxygen sensing in the hypoxic response pathway: regulation of the hypoxia-inducible transcription factor. Genes Dev 17: 2614-2623, 2003.
20. Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294: 1337-1340, 2001.
21. Bushuev VI, Miasnikova GY, Sergueeva AI, Polyakova LA, Okhotin D, Gaskin PR, Debebe Z, Nekhai S, Castro OL, Prchal JT, Gordeuk VR. Endothelin-1, vascular endothelial growth factor and systolic pulmonary artery pressure in patients with Chuvash polycythemia. Haematologica 91: 744-749, 2006.
22. Cai Z, Manalo DJ, Wei G, Rodriguez ER, Fox-Talbot K, Lu H, Zweier JL, Semenza GL. Hearts from rodents exposed to intermittent hypoxia or erythropoietin are protected against ischemia-reperfusion injury. Circulation 108: 79-85, 2003.
23. Cario H, Schwarz K, Jorch N, Kyank U, Petrides PE, Schneider DT, Uhle R, Debatin KM, Kohne E. Mutations in the von Hippel-Lindau (VHL) tumor suppressor gene and VHL-haplotype analysis in patients with presumable congenital erythrocytosis. Haematologica 90: 19-24, 2005.
24. Chavez JC, Baranova O, Lin J, Pichiule P. The transcriptional activator hypoxia inducible factor 2 (HIF-2/EPAS-1) regulates the oxygen-dependent expression of erythropoietin in cortical astrocytes. J Neurosci 26: 9471-9481, 2006.
25. Cheng J, Kang X, Zhang S, Yeh ET. SUMO-specific protease 1 is essential for stabilization of HIF1alpha during hypoxia. Cell 131: 584-595, 2007.
26. Chin K, Yu X, Beleslin-Cokic B, Liu C, Shen K, Mohrenweiser HW, Noguchi CT. Production and processing of erythropoietin receptor transcripts in brain. Brain Res Mol Brain Res 81: 29-42, 2000.
27. Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, de Cabo R, Sinclair DA. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 305: 390-392, 2004. (Pubitemid 38938153)
28. Compernolle V, Brusselmans K, Acker T, Hoet P, Tjwa M, Beck H, Plaisance S, Dor Y, Keshet E, Lupu F, Nemery B, Dewerchin M, Van Veldhoven P, Plate K, Moons L, Collen D, Carmeliet P. Loss of HIF-2alpha and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice. Nat Med 8: 702-710, 2002.
29. Dame C, Bartmann P, Wolber E, Fahnenstich H, Hofmann D, Fandrey J. Erythropoietin gene expression in different areas of the developing human central nervous system. Brain Res Dev Brain Res 125: 69-74, 2000.
30. Dame C, Fahnenstich H, Freitag P, Hofmann D, Abdul-Nour T, Bartmann P, Fandrey J. Erythropoietin mRNA expression in human fetal and neonatal tissue. Blood 92: 3218-3225, 1998.
31. Dame C, Sola MC, Lim KC, Leach KM, Fandrey J, Ma Y, Knopfle G, Engel JD, Bungert J. Hepatic erythropoietin gene regulation by GATA-4. J Biol Chem 279: 2955-2961, 2004.
32. Dioum EM, Chen R, Alexander MS, Zhang Q, Hogg RT, Gerard RD, Garcia JA. Regulation of hypoxia-inducible factor 2alpha signaling by the stress-responsive deacetylase sirtuin 1. Science 324: 1289-1293, 2009.
33. Ebert BL, Bunn HF. Regulation of the erythropoietin gene. Blood 94: 1864-1877, 1999.
34. Eckardt KU, Ratcliffe PJ, Tan CC, Bauer C, Kurtz A. Age-dependent expression of the erythropoietin gene in rat liver and kidneys. J Clin Invest 89: 753-760, 1992.
35. Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O'Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A, Tian YM, Masson N, Hamilton DL, Jaakkola P, Barstead R, Hodgkin J, Maxwell PH, Pugh CW, Schofield CJ, Ratcliffe PJ. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107: 43-54, 2001.
36. Evans RG, Gardiner BS, Smith DW, O'Connor PM. Intrarenal oxygenation: unique challenges and the biophysical basis of homeostasis. Am J Physiol Renal Physiol 295: F1259-F1270, 2008.
37. Fandrey J. Oxygen-dependent and tissue-specific regulation of erythropoietin gene expression. Am J Physiol Regul Integr Comp Physiol 286: R977-R988, 2004.
38. Fandrey J, Bunn HF. In vivo and in vitro regulation of erythropoietin mRNA: measurement by competitive polymerase chain reaction. Blood 81: 617-623, 1993. (Pubitemid 23040851)
39. Frede S, Geuting L, Freitag P, Fandrey J. Role of HIF-1 and HIF-2 for the oxygen-regulated expression of erythropietin in human kidney cells (Abstract). Am J Hematology 84: E3, 2009.
40. Fried W. The liver as a source of extrarenal erythropoietin production. Blood 40: 671-677, 1972.
41. Fried W, Kilbridge T, Krantz S, McDonald TP, Lange RD. Studies on extrarenal erythropoietin. J Lab Clin Med 73: 244-248, 1969.
42. Galson DL, Tsuchiya T, Tendler DS, Huang LE, Ren Y, Ogura T, Bunn HF. The orphan receptor hepatic nuclear factor 4 functions as a transcriptional activator for tissue-specific and hypoxia-specific erythropoietin gene expression and is antagonized by EAR3/COUP-TF1. Mol Cell Biol 15: 2135-2144, 1995.
43. Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood 102: 783-788, 2003. (Pubitemid 36917762)
44. Ganz T. Molecular control of iron transport. J Am Soc Nephrol 18: 394-400, 2007.
45. Gao J, Chen J, Kramer M, Tsukamoto H, Zhang AS, Enns CA. Interaction of the hereditary hemochromatosis protein HFE with transferrin receptor 2 is required for transferrin-induced hepcidin expression. Cell Metab 9: 217-227, 2009.
46. Gordeuk VR, Sergueeva AI, Miasnikova GY, Okhotin D, Voloshin Y, Choyke PL, Butman JA, Jedlickova K, Prchal JT, Polyakova LA. Congenital disorder of oxygen sensing: association of the homozygous Chuvash polycythemia VHL mutation with thrombosis and vascular abnormalities but not tumors. Blood 103: 3924-3932, 2004. (Pubitemid 38596314)
47. Gordeuk VR, Stockton DW, Prchal JT. Congenital polycythemias/ erythrocytoses. Haematologica 90: 109-116, 2005.
48. Gruber M, Hu CJ, Johnson RS, Brown EJ, Keith B, Simon MC. Acute postnatal ablation of Hif-2alpha results in anemia. Proc Natl Acad Sci USA 104: 2301-2306, 2007. (Pubitemid 46391392)
49. Gustafsson MV, Zheng X, Pereira T, Gradin K, Jin S, Lundkvist J, Ruas JL, Poellinger L, Lendahl U, Bondesson M. Hypoxia requires notch signaling to maintain the undifferentiated cell state. Dev Cell 9: 617-628, 2005. (Pubitemid 41555144)
50. Haase VH. Hypoxia-inducible factors in the kidney. Am J Physiol Renal Physiol 291: F271-F281, 2006.
51. Hickey MM, Lam JC, Bezman NA, Rathmell WK, Simon MC. von Hippel-Lindau mutation in mice recapitulates Chuvash polycythemia via hypoxia-inducible factor-2alpha signaling and splenic erythropoiesis. J Clin Invest 117: 3879-3889, 2007.
52. Hofer T, Wenger RH, Kramer MF, Ferreira GC, Gassmann M. Hypoxic up-regulation of erythroid 5-aminolevulinate synthase. Blood 101: 348-350, 2003. (Pubitemid 36025930)
53. Hon WC, Wilson MI, Harlos K, Claridge TD, Schofield CJ, Pugh CW, Maxwell PH, Ratcliffe PJ, Stuart DI, Jones EY. Structural basis for the recognition of hydroxyproline in HIF-1 alpha by pVHL. Nature 417: 975-978, 2002. (Pubitemid 34716877)
54. Hsieh MM, Linde NS, Wynter A, Metzger M, Wong C, Langsetmo I, Lin A, Smith R, Rodgers GP, Donahue RE, Klaus SJ, Tisdale JF. HIF prolyl hydroxylase inhibition results in endogenous erythropoietin induction, erythrocytosis, and modest fetal hemoglobin expression in rhesus macaques. Blood 110: 2140-2147, 2007.
55. Hu CJ, Wang LY, Chodosh LA, Keith B, Simon MC. Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Mol Cell Biol 23: 9361-9374, 2003.
56. 2 sensing. Science 292: 464-468, 2001.
57. 2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev 12: 149-162, 1998.
58. 2-regulated prolyl hydroxylation. Science 292: 468-472, 2001.
59. Jacobs K, Shoemaker C, Rudersdorf R, Neill SD, Kaufman RJ, Mufson A, Seehra J, Jones SS, Hewick R, Fritsch EF, Kawakita M, Shimizu T, Miyaki T. Isolation and characterization of genomic and cDNA clones of human erythropoietin. Nature 313: 806-810, 1985.
60. Jacobson LO, Goldwasser E, Fried W, Plzak L. Role of the kidney in erythropoiesis. Nature 179: 633-634, 1957.
61. Jelkmann W. Erythropoietin after a century of research: younger than ever. Eur J Haematol 78: 183-205, 2007.
62. Jelkmann W, Bohlius J, Hallek M, Sytkowski AJ. The erythropoietin receptor in normal and cancer tissues. Crit Rev Oncol Hematol 67: 39-61, 2008.
63. Jelkmann W, Wagner K. Beneficial and ominous aspects of the pleiotropic action of erythropoietin. Ann Hematol 83: 673-686, 2004. (Pubitemid 39440211)
64. Jourdanet D. Influence de la Pression de L'air sur la Vie de L'homme. Paris: Masson, 1875.
65. Kaelin WG Jr., Ratcliffe PJ. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell 30: 393-402, 2008.
66. Kang MJ, Kim HJ, Kim HK, Lee JY, Kim DH, Jung KJ, Kim KW, Baik HS, Yoo MA, Yu BP, Chung HY. The effect of age and calorie restriction on HIF-1-responsive genes in aged liver. Biogerontology 6: 27-37, 2005.
67. Kazal LA, Erslev AJ. Erythropoietin production in renal tumors. Ann Clin Lab Sci 5: 98-109, 1975.
68. Kewley RJ, Whitelaw ML, Chapman-Smith A. The mammalian basic helix-loop-helix/PAS family of transcriptional regulators. Int J Biochem Cell Biol 36: 189-204, 2004. (Pubitemid 37487755)
69. Kim WY, Safran M, Buckley MR, Ebert BL, Glickman J, Bosenberg M, Regan M, Kaelin WG Jr. Failure to prolyl hydroxylate hypoxia-inducible factor alpha phenocopies VHL inactivation in vivo. EMBO J 25: 4650-4662, 2006. (Pubitemid 44498137)
70. Kobayashi T, Yanase H, Iwanaga T, Sasaki R, Nagao M. Epididymis is a novel site of erythropoietin production in mouse reproductive organs. Biochem Biophys Res Commun 296: 145-151, 2002. (Pubitemid 35002069)
71. Koshiji M, Kageyama Y, Pete EA, Horikawa I, Barrett JC, Huang LE. HIF-1alpha induces cell cycle arrest by functionally counteracting Myc. EMBO J 23: 1949-1956, 2004.
72. Koury ST, Bondurant MC, Koury MJ. Localization of erythropoietin synthesizing cells in murine kidneys by in situ hybridization. Blood 71: 524-527, 1988.
73. Koury ST, Bondurant MC, Koury MJ, Semenza GL. Localization of cells producing erythropoietin in murine liver by in situ hybridization. Blood 77: 2497-2503, 1991.
74. Koury ST, Koury MJ, Bondurant MC, Caro J, Graber SE. Quantitation of erythropoietin-producing cells in kidneys of mice by in situ hybridization: correlation with hematocrit, renal erythropoietin mRNA, and serum erythropoietin concentration. Blood 74: 645-651, 1989. (Pubitemid 19208805)
75. Lacombe C, Da Silva JL, Bruneval P, Fournier JG, Wendling F, Casadevall N, Camilleri JP, Bariety J, Varet B, Tambourin P. Peritubular cells are the site of erythropoietin synthesis in the murine hypoxic kidney. J Clin Invest 81: 620-623, 1988.
76. Lakhal S, Talbot NP, Crosby A, Stoepker C, Townsend AR, Robbins PA, Pugh CW, Ratcliffe PJ, Mole DR. Regulation of growth differentiation factor 15 expression by intracellular iron. Blood 113: 1555-1563, 2009.
77. Lando D, Peet DJ, Gorman JJ, Whelan DA, Whitelaw ML, Bruick RK. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev 16: 1466-1471, 2002.
78. Lando D, Peet DJ, Whelan DA, Gorman JJ, Whitelaw ML. Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science 295: 858-861, 2002.
79. Lee PJ, Jiang BH, Chin BY, Iyer NV, Alam J, Semenza GL, Choi AM. Hypoxia-inducible factor-1 mediates transcriptional activation of the heme oxygenase-1 gene in response to hypoxia. J Biol Chem 272: 5375-5381, 1997.
80. Levine RL. Janus kinase mutations. Semin Oncol 36: S6-S11, 2009.
81. Lin FK, Suggs S, Lin CH, Browne JK, Smalling R, Egrie JC, Chen KK, Fox GM, Martin F, Stabinsky Z, Badrawi SM, Lai PH, Goldwasser E. Cloning and expression of the human erythropoietin gene. Proc Natl Acad Sci USA 82: 7580-7584, 1985.
82. Liu E, Percy MJ, Amos CI, Guan Y, Shete S, Stockton DW, McMullin MF, Polyakova LA, Ang SO, Pastore YD, Jedlickova K, Lappin TR, Gordeuk V, Prchal JT. The worldwide distribution of the VHL 598C>T mutation indicates a single founding event. Blood 103: 1937-1940, 2004.
83. Liu YL, Ang SO, Weigent DA, Prchal JT, Bloomer JR. Regulation of ferrochelatase gene expression by hypoxia. Life Sci 75: 2035-2043, 2004.
84. Lok CN, Ponka P. Identification of a hypoxia response element in the transferrin receptor gene. J Biol Chem 274: 24147-24152, 1999.
85. Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM, Oldfield EH. von Hippel-Lindau disease. Lancet 361: 2059-2067, 2003.
86. Macdougall IC, Ashenden M. Current and upcoming erythropoiesis- stimulating agents, iron products, and other novel anemia medications. Adv Chronic Kidney Dis 16: 117-130, 2009.
87. Magnanti M, Gandini O, Giuliani L, Gazzaniga P, Marti HH, Gradilone A, Frati L, Agliano AM, Gassmann M. Erythropoietin expression in primary rat Sertoli and peritubular myoid cells. Blood 98: 2872-2874, 2001.
88. Mahon PC, Hirota K, Semenza GL. FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev 15: 2675-2686, 2001. (Pubitemid 32988878)
89. Makino Y, Cao R, Svensson K, Bertilsson G, Asman M, Tanaka H, Cao Y, Berkenstam A, Poellinger L. Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression. Nature 414: 550-554, 2001. (Pubitemid 33131538)
90. Manalo DJ, Rowan A, Lavoie T, Natarajan L, Kelly BD, Ye SQ, Garcia JG, Semenza GL. Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1. Blood 105: 659-669, 2005. (Pubitemid 40070750)
91. Marti HH, Gassmann M, Wenger RH, Kvietikova I, Morganti-Kossmann MC, Kossmann T, Trentz O, Bauer C. Detection of erythropoietin in human liquor: intrinsic erythropoietin production in the brain. Kidney Int 51: 416-418, 1997. (Pubitemid 27088152)
92. Marti HH, Wenger RH, Rivas LA, Straumann U, Digicaylioglu M, Henn V, Yonekawa Y, Bauer C, Gassmann M. Erythropoietin gene expression in human, monkey and murine brain. Eur J Neurosci 8: 666-676, 1996. (Pubitemid 26114611)
93. Masson N, Willam C, Maxwell PH, Pugh CW, Ratcliffe PJ. Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation. EMBO J 20: 5197-5206, 2001. (Pubitemid 32910914)
94. Mastrogiannaki M, Matak P, Keith B, Simon MC, Vaulont S, Peyssonnaux C. HIF-2alpha, but not HIF-1alpha, promotes iron absorption in mice. J Clin Invest 119: 1159-1166, 2009.
95. Masuda S, Kobayashi T, Chikuma M, Nagao M, Sasaki R. The oviduct produces erythropoietin in an estrogen- and oxygen-dependent manner. Am J Physiol Endocrinol Metab 278: E1038-E1044, 2000. (Pubitemid 30439141)
96. Maxwell PH, Ferguson DJ, Osmond MK, Pugh CW, Heryet A, Doe BG, Johnson MH, Ratcliffe PJ. Expression of a homologously recombined erythopoietin-SV40 T antigen fusion gene in mouse liver: evidence for erythropoietin production by Ito cells. Blood 84: 1823-1830, 1994.
97. Maxwell PH, Osmond MK, Pugh CW, Heryet A, Nicholls LG, Tan CC, Doe BG, Ferguson DJ, Johnson MH, Ratcliffe PJ. Identification of the renal erythropoietin-producing cells using transgenic mice. Kidney Int 44: 1149-1162, 1993. (Pubitemid 23316488)
98. Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis [see comments]. Nature 399: 271-275, 1999.
99. Maynard MA, Evans AJ, Shi W, Kim WY, Liu FF, Ohh M. Dominant-negative HIF-3 alpha 4 suppresses VHL-null renal cell carcinoma progression. Cell Cycle 6: 2810-2816, 2007.
100. Maynard MA, Qi H, Chung J, Lee EH, Kondo Y, Hara S, Conaway RC, Conaway JW, Ohh M. Multiple splice variants of the human HIF-3alpha locus are targets of the VHL E3 ubiquitin ligase complex. J Biol Chem 278: 1032-1040, 2003.
101. McMahon S, Grondin F, McDonald PP, Richard DE, Dubois CM. Hypoxia-enhanced expression of the proprotein convertase furin is mediated by hypoxia-inducible factor-1: impact on the bioactivation of proproteins. J Biol Chem 280: 6561-6569, 2005.
102. Meynard D, Kautz L, Darnaud V, Canonne-Hergaux F, Coppin H, Roth MP. Lack of the bone morphogenetic protein BMP6 induces massive iron overload. Nat Genet 41: 478-481, 2009.
103. Minamishima YA, Moslehi J, Bardeesy N, Cullen D, Bronson RT, Kaelin WG Jr. Somatic inactivation of the PHD2 prolyl hydroxylase causes polycythemia and congestive heart failure. Blood 111: 3236-3244, 2008.
104. Minamishima YA, Moslehi J, Padera RF, Bronson RT, Liao R, Kaelin WG Jr. A feedback loop involving the Phd3 prolyl hydroxylase tunes the mammalian hypoxic response in vivo. Mol Cell Biol 29: 5729-5741, 2009.
105. Miyake T, Kung CK, Goldwasser E. Purification of human erythropoietin. J Biol Chem 252: 5558-5564, 1977.
106. Morita M, Ohneda O, Yamashita T, Takahashi S, Suzuki N, Nakajima O, Kawauchi S, Ema M, Shibahara S, Udono T, Tomita K, Tamai M, Sogawa K, Yamamoto M, Fujii-Kuriyama Y. HLF/HIF-2alpha is a key factor in retinopathy of prematurity in association with erythropoietin. EMBO J 22: 1134-1146, 2003.
107. Moritz KM, Lim GB, Wintour EM. Developmental regulation of erythropoietin and erythropoiesis. Am J Physiol Regul Integr Comp Physiol 273: R1829-R1844, 1997.
108. Muckenthaler MU, Galy B, Hentze MW. Systemic iron homeostasis and the iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network. Annu Rev Nutr 28: 197-213, 2008.
109. Mukhopadhyay CK, Mazumder B, Fox PL. Role of hypoxia-inducible factor-1 in transcriptional activation of ceruloplasmin by iron deficiency. J Biol Chem 275: 21048-21054, 2000.
110. Nakayama K, Frew IJ, Hagensen M, Skals M, Habelhah H, Bhoumik A, Kadoya T, Erdjument-Bromage H, Tempst P, Frappell PB, Bowtell DD, Ronai Z. Siah2 regulates stability of prolyl-hydroxylases, controls HIF1alpha abundance, and modulates physiological responses to hypoxia. Cell 117: 941-952, 2004.
111. Nakayama K, Qi J, Ronai Z. The ubiquitin ligase Siah2 and the hypoxia response. Mol Cancer Res 7: 443-451, 2009.
112. Nicolas G, Chauvet C, Viatte L, Danan JL, Bigard X, Devaux I, Beaumont C, Kahn A, Vaulont S. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest 110: 1037-1044, 2002.
113. Obara N, Suzuki N, Kim K, Nagasawa T, Imagawa S, Yamamoto M. Repression via the GATA box is essential for tissue-specific erythropoietin gene expression. Blood 111: 5223-5232, 2008.
114. Pagel H, Jelkmann W, Weiss C. A comparison of the effects of renal artery constriction and anemia on the production of erythropoietin. Pflügers Arch 413: 62-66, 1988.
115. Peng J, Zhang L, Drysdale L, Fong GH. The transcription factor EPAS-1/hypoxia-inducible factor 2alpha plays an important role in vascular remodeling. Proc Natl Acad Sci USA 97: 8386-8391, 2000.
116. Percy MJ, Beer PA, Campbell G, Dekker AW, Green AR, Oscier D, Rainey MG, van Wijk R, Wood M, Lappin TR, McMullin MF, Lee FS. Novel exon 12 mutations in the HIF2A gene associated with erythrocytosis. Blood 111: 5400-5402, 2008.
117. Percy MJ, Furlow PW, Beer PA, Lappin TR, McMullin MF, Lee FS. A novel erythrocytosis-associated PHD2 mutation suggests the location of a HIF binding groove. Blood 110: 2193-2196, 2007.
118. Percy MJ, Furlow PW, Lucas GS, Li X, Lappin TR, McMullin MF, Lee FS. A gain-of-function mutation in the HIF2A gene in familial erythrocytosis. N Engl J Med 358: 162-168, 2008.
119. Percy MJ, McMullin MF, Jowitt SN, Potter M, Treacy M, Watson WH, Lappin TR. Chuvash-type congenital polycythemia in 4 families of Asian and Western European ancestry. Blood 102: 1097-1099, 2003.
120. Percy MJ, Zhao Q, Flores A, Harrison C, Lappin TR, Maxwell PH, McMullin MF, Lee FS. A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis. Proc Natl Acad Sci USA 103: 654-659, 2006.
121. Perrotta S, Nobili B, Ferraro M, Migliaccio C, Borriello A, Cucciolla V, Martinelli V, Rossi F, Punzo F, Cirillo P, Parisi G, Zappia V, Rotoli B, Ragione FD. Von Hippel-Lindau-dependent polycythemia is endemic on the island of Ischia: identification of a novel cluster. Blood 107: 514-519, 2006.
122. Peyssonnaux C, Zinkernagel AS, Schuepbach RA, Rankin E, Vaulont S, Haase VH, Nizet V, Johnson RS. Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J Clin Invest 117: 1926-1932, 2007.
123. Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU, Feyzi JM, Ivanovich P, Kewalramani R, Levey AS, Lewis EF, McGill JB, McMurray JJ, Parfrey P, Parving HH, Remuzzi G, Singh AK, Solomon SD, Toto R. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 361: 2019-2032, 2009.
124. Plotkin MD, Goligorsky MS. Mesenchymal cells from adult kidney support angiogenesis and differentiate into multiple interstitial cell types including erythropoietin-producing fibroblasts. Am J Physiol Renal Physiol 291: F902-F912, 2006.
125. Rankin EB, Biju MP, Liu Q, Unger TL, Rha J, Johnson RS, Simon MC, Keith B, Haase VH. Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo. J Clin Invest 117: 1068-1077, 2007. (Pubitemid 46556763)
126. Ravi R, Mookerjee B, Bhujwalla ZM, Sutter CH, Artemov D, Zeng Q, Dillehay LE, Madan A, Semenza GL, Bedi A. Regulation of tumor angiogenesis by p53-induced degradation of hypoxia- inducible factor 1alpha. Genes Dev 14: 34-44, 2000.
127. Rolfs A, Kvietikova I, Gassmann M, Wenger RH. Oxygen-regulated transferrin expression is mediated by hypoxia-inducible factor-1. J Biol Chem 272: 20055-20062, 1997. (Pubitemid 27340110)
128. Rosenberger C, Mandriota S, Jurgensen JS, Wiesener MS, Horstrup JH, Frei U, Ratcliffe PJ, Maxwell PH, Bachmann S, Eckardt KU. Expression of hypoxia-inducible factor-1alpha and -2alpha in hypoxic and ischemic rat kidneys. J Am Soc Nephrol 13: 1721-1732, 2002. (Pubitemid 34700596)
129. Ryan HE, Lo J, Johnson RS. HIF-1 alpha is required for solid tumor formation and embryonic vascularization. EMBO J 17: 3005-3015, 1998. (Pubitemid 28254373)
130. Salahudeen AA, Thompson JW, Ruiz JC, Ma HW, Kinch LN, Li Q, Grishin NV, Bruick RK. An E3 ligase possessing an iron-responsive hemerythrin domain is a regulator of iron homeostasis. Science 326: 722-726, 2009.
131. Sanchez M, Galy B, Muckenthaler MU, Hentze MW. Iron-regulatory proteins limit hypoxia-inducible factor-2alpha expression in iron deficiency. Nat Struct Mol Biol 14: 420-426, 2007. (Pubitemid 46685876)
132. Schofield CJ, Ratcliffe PJ. Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol 5: 343-354, 2004.
133. Scortegagna M, Ding K, Oktay Y, Gaur A, Thurmond F, Yan LJ, Marck BT, Matsumoto AM, Shelton JM, Richardson JA, Bennett MJ, Garcia JA. Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1-/- mice. Nat Genet 35: 331-340, 2003.
134. Scortegagna M, Ding K, Zhang Q, Oktay Y, Bennett MJ, Bennett M, Shelton JM, Richardson JA, Moe O, Garcia JA. HIF-2alpha regulates murine hematopoietic development in an erythropoietin-dependent manner. Blood 105: 3133-3140, 2005.
135. Scortegagna M, Morris MA, Oktay Y, Bennett M, Garcia JA. The HIF family member EPAS1/HIF-2alpha is required for normal hematopoiesis in mice. Blood 102: 1634-1640, 2003.
136. Semenza GL. HIF-1 and mechanisms of hypoxia sensing. Curr Opin Cell Biol 13: 167-171, 2001.
137. Semenza GL. Regulation of mammalian O2 homeostasis by hypoxiai-nducible factor 1. Annu Rev Cell Dev Biol 15: 551-578, 1999.
138. Semenza GL, Dureza RC, Traystman MD, Gearhart JD, Antonarakis SE. Human erythropoietin gene expression in transgenic mice: multiple transcription initiation sites and cis-acting regulatory elements. Mol Cell Biol 10: 930-938, 1990. (Pubitemid 120004682)
139. Semenza GL, Koury ST, Nejfelt MK, Gearhart JD, Antonarakis SE. Cell-type-specific and hypoxia-inducible expression of the human erythropoietin gene in transgenic mice. Proc Natl Acad Sci USA 88: 8725-8729, 1991.
140. Semenza GL, Traystman MD, Gearhart JD, Antonarakis SE. Polycythemia in transgenic mice expressing the human erythropoietin gene. Proc Natl Acad Sci USA 86: 2301-2305, 1989.
141. Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 12: 5447-5454, 1992.
142. Shah YM, Matsubara T, Ito S, Yim SH, Gonzalez FJ. Intestinal hypoxia-inducible transcription factors are essential for iron absorption following iron deficiency. Cell Metab 9: 152-164, 2009.
143. Silvestri L, Pagani A, Camaschella C. Furin-mediated release of soluble hemojuvelin: a new link between hypoxia and iron homeostasis. Blood 111: 924-931, 2008.
144. Smith TG, Brooks JT, Balanos GM, Lappin TR, Layton DM, Leedham DL, Liu C, Maxwell PH, McMullin MF, McNamara CJ, Percy MJ, Pugh CW, Ratcliffe PJ, Talbot NP, Treacy M, Robbins PA. Mutation of von Hippel-Lindau tumour suppressor and human cardiopulmonary physiology. PLoS Med 3: e290, 2006.
145. Spivak JL, Gascon P, Ludwig H. Anemia management in oncology and hematology. Oncologist 14, Suppl 1: 43-56, 2009.
146. Stebbins CE, Kaelin WG Jr, Pavletich NP. Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function. Science 284: 455-461, 1999.
147. Stolze IP, Tian YM, Appelhoff RJ, Turley H, Wykoff CC, Gleadle JM, Ratcliffe PJ. Genetic analysis of the role of the asparaginyl hydroxylase factor inhibiting hypoxia-inducible factor (HIF) in regulating HIF transcriptional target genes. J Biol Chem 279: 42719-42725, 2004. (Pubitemid 39372158)
148. Tacchini L, Bianchi L, Bernelli-Zazzera A, Cairo G. Transferrin receptor induction by hypoxia. HIF-1-mediated transcriptional activation and cell-specific post-transcriptional regulation. J Biol Chem 274: 24142-24146, 1999. (Pubitemid 129528460)
149. Takeda K, Aguila HL, Parikh NS, Li X, Lamothe K, Duan LJ, Takeda H, Lee FS, Fong GH. Regulation of adult erythropoiesis by prolyl hydroxylase domain proteins. Blood 111: 3229-3235, 2008.
150. Takeda K, Cowan A, Fong GH. Essential role for prolyl hydroxylase domain protein 2 in oxygen homeostasis of the adult vascular system. Circulation 116: 774-781, 2007. (Pubitemid 47255995)
151. Takeda K, Ho VC, Takeda H, Duan LJ, Nagy A, Fong GH. Placental but not heart defects are associated with elevated hypoxia-inducible factor alpha levels in mice lacking prolyl hydroxylase domain protein 2. Mol Cell Biol 26: 8336-8346, 2006. (Pubitemid 44748568)
152. Tanno T, Bhanu NV, Oneal PA, Goh SH, Staker P, Lee YT, Moroney JW, Reed CH, Luban NL, Wang RH, Eling TE, Childs R, Ganz T, Leitman SF, Fucharoen S, Miller JL. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med 13: 1096-1101, 2007.
153. Tian H, Hammer RE, Matsumoto AM, Russell DW, McKnight SL. The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development. Genes Dev 12: 3320-3324, 1998.
154. Vashisht AA, Zumbrennen KB, Huang X, Powers DN, Durazo A, Sun D, Bhaskaran N, Persson A, Uhlen M, Sangfelt O, Spruck C, Leibold EA, Wohlschlegel JA. Control of iron homeostasis by an iron-regulated ubiquitin ligase. Science 326: 718-721, 2009.
155. Viault F. Sur laugmentation considérable du nombre des globules rouges dans le sang chez les inhabitants des hauts plateaux de l'Amérique du Sud. C R Acad Sci Paris 111: 917-918, 1890.
156. Volke M, Gale DP, Maegdefrau U, Schley G, Klanke B, Bosserhoff AK, Maxwell PH, Eckardt KU, Warnecke C. Evidence for a lack of a direct transcriptional suppression of the iron regulatory peptide hepcidin by hypoxia-inducible factors. PLoS ONE 4: e7875, 2009.
157. von Wussow U, Klaus J, Pagel H. Is the renal production of erythropoietin controlled by the brain stem? Am J Physiol Endocrinol Metab 289: E82-E86, 2005.
158. 2 tension. Proc Natl Acad Sci USA 92: 5510-5514, 1995.
159. Wang GL, Semenza GL. Purification and characterization of hypoxia-inducible factor 1. J Biol Chem 270: 1230-1237, 1995.
160. Warnecke C, Zaborowska Z, Kurreck J, Erdmann VA, Frei U, Wiesener M, Eckardt KU. Differentiating the functional role of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha (EPAS-1) by the use of RNA interference: erythropoietin is a HIF-2alpha target gene in Hep3B and Kelly cells. FASEB J 18: 1462-1464, 2004.
161. Weidemann A, Kerdiles YM, Knaup KX, Rafie CA, Boutin AT, Stockmann C, Takeda N, Scadeng M, Shih AY, Haase VH, Simon MC, Kleinfeld D, Johnson RS. The glial cell response is an essential component of hypoxia-induced erythropoiesis in mice. J Clin Invest 119: 3373-3383, 2009.
162. Wenger RH, Stiehl DP, Camenisch G. Integration of oxygen signaling at the consensus HRE. Sci STKE 2005: re12, 2005.
163. Wiesener MS, Jurgensen JS, Rosenberger C, Scholze CK, Horstrup JH, Warnecke C, Mandriota S, Bechmann I, Frei UA, Pugh CW, Ratcliffe PJ, Bachmann S, Maxwell PH, Eckardt KU. Widespread hypoxia-inducible expression of HIF-2alpha in distinct cell populations of different organs. FASEB J 17: 271-273, 2003.
164. Yamashita T, Ohneda O, Sakiyama A, Iwata F, Ohneda K, Fujii-Kuriyama Y. The microenvironment for erythropoiesis is regulated by HIF-2alpha through VCAM-1 in endothelial cells. Blood 112: 1482-1492, 2008.
165. Yasuda Y, Masuda S, Chikuma M, Inoue K, Nagao M, Sasaki R. Estrogen-dependent production of erythropoietin in uterus and its implication in uterine angiogenesis. J Biol Chem 273: 25381-25387, 1998.
166. Yoon D, Pastore YD, Divoky V, Liu E, Mlodnicka AE, Rainey K, Ponka P, Semenza GL, Schumacher A, Prchal JT. HIF-1alpha -deficiency results in dysregulated EPO signaling and iron homeostasis in mouse development. J Biol Chem 281: 25703-25711, 2006.
167. Yu AY, Shimoda LA, Iyer NV, Huso DL, Sun X, McWilliams R, Beaty T, Sham JS, Wiener CM, Sylvester JT, Semenza GL. Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1alpha. J Clin Invest 103: 691-696, 1999.
168. Yu F, White SB, Zhao Q, Lee FS. HIF-1alpha binding to VHL is regulated by stimulus-sensitive proline hydroxylation. Proc Natl Acad Sci USA 98: 9630-9635, 2001. (Pubitemid 32769354)
169. Zanjani ED, Ascensao JL, McGlave PB, Banisadre M, Ash RC. Studies on the liver to kidney switch of erythropoietin production. J Clin Invest 67: 1183-1188, 1981.
170. Zimmer M, Ebert BL, Neil C, Brenner K, Papaioannou I, Melas A, Tolliday N, Lamb J, Pantopoulos K, Golub T, Iliopoulos O. Small-molecule inhibitors of HIF-2a translation link its 5′UTR iron-responsive element to oxygen sensing. Mol Cell 32: 838-848, 2008.