Renal erythropoietin-producing cells in health and disease

Frontiers in Physiology

Volumn 6, Issue JUN, 2015, Pages

  Souma, Tomokazu ^a,b   Suzuki, Norio ^a   Yamamoto, Masayuki ^a  

^a TOHOKU UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

^b NORTHWESTERN UNIVERSITY   (United States)

Author keywords

Erythropoietin; Fibrosis; Hypoxia; Plasticity; Renal Epo producing cell (REP)

Indexed keywords

CRE RECOMBINASE; ERYTHROPOIETIN; HEPATOCYTE NUCLEAR FACTOR 4; HYPOXIA INDUCIBLE FACTOR 1ALPHA; HYPOXIA INDUCIBLE FACTOR 1BETA; HYPOXIA INDUCIBLE FACTOR 2ALPHA; HYPOXIA INDUCIBLE FACTOR 3ALPHA; HYPOXIA INDUCIBLE FACTOR PROLINE DIOXYGENASE; HYPOXIA INDUCIBLE FACTOR PROLINE DIOXYGENASE 1; HYPOXIA INDUCIBLE FACTOR PROLINE DIOXYGENASE 2; HYPOXIA INDUCIBLE FACTOR PROLINE DIOXYGENASE 3; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; RETINOID X RECEPTOR; TRANSFORMING GROWTH FACTOR BETA; UNCLASSIFIED DRUG; VON HIPPEL LINDAU PROTEIN;

ANEMIA; BINDING SITE; CELL COMMUNICATION; CELL PROLIFERATION; CELL TRANSFORMATION; DNA METHYLATION; EPO GENE; ERYTHROID PRECURSOR CELL; GENE; GENE EXPRESSION REGULATION; GENE LOCUS; GENETIC TRANSCRIPTION; HUMAN; KIDNEY FIBROSIS; MYOFIBROBLAST; NONHUMAN; OXYGEN CONSUMPTION; OXYGEN SUPPLY; PATHOGENESIS; PLASTICITY; PROTEIN DEGRADATION; PROTEIN EXPRESSION; PROTEIN SECRETION; PROTEIN SYNTHESIS; REVIEW; TRANSCRIPTION END SITE; TRANSCRIPTION REGULATION; UPREGULATION;

EID: 84940029720     PISSN: None     EISSN: 1664042X     Source Type: Journal    
DOI: 10.3389/fphys.2015.00167     Document Type: Review

References (87)

1. Asada, N., Takase, M., Nakamura, J., Oguchi, A., Asada, M., Suzuki, N., et al. (2011). Dysfunction of fibroblasts of extrarenal origin underlies renal fibrosis and renal anemia in mice. J. Clin. Invest. 121, 3981-3990. doi: 10.1172/JCI57301.
2. Bechtel, W., McGoohan, S., Zeisberg, E. M., Muller, G. A., Kalbacher, H., Salant, D. J., et al. (2010). Methylation determines fibroblast activation and fibrogenesis in the kidney. Nat. Med. 16, 544-550. doi: 10.1038/nm.2135.
3. Bernhardt, W. M., Wiesener, M. S., Scigalla, P., Chou, J., Schmieder, R. E., Gunzler, V., et al. (2010). Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD. J. Am. Soc. Nephrol. 21, 2151-2156. doi: 10.1681/ASN.2010010116.
4. Boor, P., and Floege, J. (2012). The renal (myo-)fibroblast: a heterogeneous group of cells. Nephrol. Dial. Transplant. 27, 3027-3036. doi: 10.1093/ndt/gfs296.
5. Boutin, A. T., Weidemann, A., Fu, Z., Mesropian, L., Gradin, K., Jamora, C., et al. (2008). Epidermal sensing of oxygen is essential for systemic hypoxic response. Cell 133, 223-334. doi: 10.1016/j.cell.2008.02.038.
6. Broekema, M., Harmsen, M. C., Koerts, J. A., van Kooten, T. G., Navis, G., van Luyn, M. J., et al. (2007). Tubular engraftment and myofibroblast differentiation of recipient-derived cells after experimental kidney transplantation. Transplantation 84, 1003-1011. doi: 10.1097/01.tp.0000285298.05242.f1.
7. Bunn, H. F. (2013). Erythropoietin. Cold Spring Harb. Perspect. Med. 3:a011619. doi: 10.1101/cshperspect.a011619.
8. Campanholle, G., Mittelsteadt, K., Nakagawa, S., Kobayashi, A., Lin, S. L., Gharib, S. A., et al. (2013). TLR-2/TLR-4 TREM-1 signaling pathway is dispensable in inflammatory myeloid cells during sterile kidney injury. PLoS ONE 8:e68640. doi: 10.1371/journal.pone.0068640.
9. Chiang, C. K., Tanaka, T., Inagi, R., Fujita, T., and Nangaku, M. (2011). Indoxyl sulfate, a representative uremic toxin, suppresses erythropoietin production in a HIF-dependent manner. Lab Invest. 91, 1564-1571. doi: 10.1038/labinvest.2011.114.
10. Dimke, H., Sparks, M. A., Thomson, B. R., Frische, S., Coffman, T. M., and Quaggin, S. E. (2015). Tubulovascular cross-talk by vascular endothelial growth factor a maintains peritubular microvasculature in kidney. J. Am. Soc. Nephrol. 26, 1027-1038. doi: 10.1681/ASN.2014010060.
11. Ding, M., Cui, S., Li, C., Jothy, S., Haase, V., Steer, B. M., et al. (2006). Loss of the tumor suppressor Vhlh leads to upregulation of Cxcr4 and rapidly progressive glomerulonephritis in mice. Nat. Med. 12, 1081-1087. doi: 10.1038/nm1460.
12. Eckardt, K. U., Koury, S. T., Tan, C. C., Schuster, S. J., Kaissling, B., Ratcliffe, P. J., et al. (1993). Distribution of erythropoietin producing cells in rat kidneys during hypoxic hypoxia. Kidney Int. 43, 815-823. doi: 10.1038/ki.1993.115.
13. Fahling, M., Mathia, S., Paliege, A., Koesters, R., Mrowka, R., Peters, H., et al. (2013). Tubular von Hippel-Lindau knockout protects against rhabdomyolysis-induced AKI. J. Am. Soc. Nephrol. 24, 1806-1819. doi: 10.1681/asn.2013030281.
14. Fioretto, P., Sutherland, D. E., Najafian, B., and Mauer, M. (2006). Remodeling of renal interstitial and tubular lesions in pancreas transplant recipients. Kidney Int. 69, 907-912. doi: 10.1038/sj.ki.5000153.
15. Friedman, S. L., Sheppard, D., Duffield, J. S., and Violette, S. (2013). Therapy for fibrotic diseases: nearing the starting line. Sci. Transl. Med. 5:167sr1. doi: 10.1126/scitranslmed.3004700.
16. Fujiu, K., Manabe, I., and Nagai, R. (2011). Renal collecting duct epithelial cells regulate inflammation in tubulointerstitial damage in mice. J. Clin. Invest. 121, 3425-3441. doi: 10.1172/JCI57582.
17. Galson, D. L., Tsuchiya, T., Tendler, D. S., Huang, L. E., Ren, Y., Ogura, T., et al. (1995). 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.
18. Goldberg, M. A., Glass, G. A., Cunningham, J. M., and Bunn, H. F. (1987). The regulated expression of erythropoietin by two human hepatoma cell lines. Proc. Natl. Acad. Sci. U.S.A. 84, 7972-7976. doi: 10.1073/pnas.84.22.7972.
19. Grgic, I., Campanholle, G., Bijol, V., Wang, C., Sabbisetti, V. S., Ichimura, T., et al. (2012). Targeted proximal tubule injury triggers interstitial fibrosis and glomerulosclerosis. Kidney Int. 82, 172-183. doi: 10.1038/ki.2012.20.
20. Gruber, M., Hu, C. J., Johnson, R. S., Brown, E. J., Keith, B., and Simon, M. C. (2007). Acute postnatal ablation of Hif-2alpha results in anemia. Proc. Natl. Acad. Sci. U.S.A. 104, 2301-2306. doi: 10.1073/pnas.0608382104.
21. Haase, V. H. (2010). Hypoxic regulation of erythropoiesis and iron metabolism. Am. J. Physiol. Renal. Physiol. 299, F1-F13. doi: 10.1152/ajprenal.00174.2010.
22. Higgins, D. F., Kimura, K., Bernhardt, W. M., Shrimanker, N., Akai, Y., Hohenstein, B., et al. (2007). Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J. Clin. Invest. 117, 3810-3820. doi: 10.1172/jci30487.
23. Humphreys, B. D., Lin, S. L., Kobayashi, A., Hudson, T. E., Nowlin, B. T., Bonventre, J. V., et al. (2010). Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am. J. Pathol. 176, 85-97. doi: 10.2353/ajpath.2010.090517.
24. Humphreys, B. D., Xu, F., Sabbisetti, V., Grgic, I., Naini, S. M., Wang, N., et al. (2013). Chronic epithelial kidney injury molecule-1 expression causes murine kidney fibrosis. J. Clin. Invest. 123, 4023-4035. doi: 10.1172/JCI45361.
25. Imagawa, S., Goldberg, M. A., Doweiko, J., and Bunn, H. F. (1991). Regulatory elements of the erythropoietin gene. Blood 77, 278-285.
26. Inomata, S., Itoh, M., Imai, H., and Sato, T. (1997). Serum levels of erythropoietin as a novel marker reflecting the severity of diabetic nephropathy. Nephron 75, 426-430. doi: 10.1159/000189580.
27. Iwano, M., Plieth, D., Danoff, T. M., Xue, C., Okada, H., and Neilson, E. G. (2002). Evidence that fibroblasts derive from epithelium during tissue fibrosis. J. Clin. Invest. 110, 341-350. doi: 10.1172/JCI0215518.
28. Jacobs, K., Shoemaker, C., Rudersdorf, R., Neill, S. D., Kaufman, R. J., Mufson, A., et al. (1985). Isolation and characterization of genomic and cDNA clones of human erythropoietin. Nature 313, 806-810. doi: 10.1038/313806a0.
29. Jelkmann, W. (2002). The enigma of the metabolic fate of circulating erythropoietin (Epo) in view of the pharmacokinetics of the recombinant drugs rhEpo and NESP. Eur. J. Haematol. 69, 265-274. doi: 10.1034/j.1600-0609.2002.02813.x.
30. Kang, H. M., Ahn, S. H., Choi, P., Ko, Y. A., Han, S. H., Chinga, F., et al. (2015). Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development. Nat. Med. 21, 37-46. doi: 10.1038/nm.3762.
31. Kapitsinou, P. P., Sano, H., Michael, M., Kobayashi, H., Davidoff, O., Bian, A., et al. (2014). Endothelial HIF-2 mediates protection and recovery from ischemic kidney injury. J. Clin. Invest. 124, 2396-2409. doi: 10.1172/JCI69073.
32. Kisseleva, T., Cong, M., Paik, Y., Scholten, D., Jiang, C., Benner, C., et al. (2012). Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis. Proc. Natl. Acad. Sci. U.S.A. 109, 9448-9453. doi: 10.1073/pnas.1201840109.
33. Kobayashi, H., Gilbert, V., Liu, Q., Kapitsinou, P. P., Unger, T. L., Rha, J., et al. (2012). Myeloid cell-derived hypoxia-inducible factor attenuates inflammation in unilateral ureteral obstruction-induced kidney injury. J. Immunol. 188, 5106-5115. doi: 10.4049/jimmunol.1103377.
34. Koesters, R., Kaissling, B., Lehir, M., Picard, N., Theilig, F., Gebhardt, R., et al. (2010). Tubular overexpression of transforming growth factor-beta1 induces autophagy and fibrosis but not mesenchymal transition of renal epithelial cells. Am. J. Pathol. 177, 632-643. doi: 10.2353/ajpath.2010.091012.
35. Koury, M. J. (2005). Erythropoietin: the story of hypoxia and a finely regulated hematopoietic hormone. Exp. Hematol. 33, 1263-1270. doi: 10.1016/j.exphem.2005.06.031.
36. Koury, S. T., Koury, M. J., Bondurant, M. C., Caro, J., and Graber, S. E. (1989). 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.
37. Kramann, R., Schneider, R. K., Dirocco, D. P., Machado, F., Fleig, S., Bondzie, P. A., et al. (2015). Perivascular gli1(+) progenitors are key contributors to injury-induced organ fibrosis. Cell Stem Cell 16, 51-66. doi: 10.1016/j.stem.2014.11.004.
38. Kuo, C. C., Lee, C. T., Chuang, C. H., Su, Y., and Chen, J. B. (2005). Recombinant human erythropoietin independence in chronic hemodialysis patients: clinical features, iron homeostasis and erythropoiesis. Clin. Nephrol. 63, 92-97. doi: 10.5414/CNP63092.
39. LeBleu, V. S., Taduri, G., O'Connell, J., Teng, Y., Cooke, V. G., Woda, C., et al. (2013). Origin and function of myofibroblasts in kidney fibrosis. Nat. Med. 19, 1047-1053. doi: 10.1038/nm.3218.
40. Li, L., Zepeda-Orozco, D., Black, R., and Lin, F. (2010). Autophagy is a component of epithelial cell fate in obstructive uropathy. Am. J. Pathol. 176, 1767-1778. doi: 10.2353/ajpath.2010.090345.
41. Lin, F. K., Suggs, S., Lin, C. H., Browne, J. K., Smalling, R., Egrie, J. C., et al. (1985). Cloning and expression of the human erythropoietin gene. Proc. Natl. Acad. Sci. U.S.A. 82, 7580-7584. doi: 10.1073/pnas.82.22.7580.
42. Lin, S. L., Castaño, A. P., Nowlin, B. T., Lupher, M. L. Jr., and Duffield, J. S. (2009). Bone marrow Ly6Chigh monocytes are selectively recruited to injured kidney and differentiate into functionally distinct populations. J. Immunol. 183, 6733-6743. doi: 10.4049/jimmunol.0901473.
43. Lin, S. L., Kisseleva, T., Brenner, D. A., and Duffield, J. S. (2008). Pericytes and perivascular fibroblasts are the primary source of collagen-producing cells in obstructive fibrosis of the kidney. Am. J. Pathol. 173, 1617-1627. doi: 10.2353/ajpath.2008.080433.
44. Mack, M., and Yanagita, M. (2014). Origin of myofibroblasts and cellular events triggering fibrosis. Kidney Int. doi: 10.1038/ki.2014.287.
45. Madan, A., Lin, C., Hatch, S. L., and Curtin, P. T. (1995). Regulated basal, inducible, and tissue-specific human erythropoietin gene-expression in transgenic mice requires multiple cis DNA-sequences. Blood 85, 2735-2741.
46. Mahon, P. C., Hirota, K., and Semenza, G. L. (2001). 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. doi: 10.1101/gad.924501.
47. Makita, T., Hernandez-Hoyos, G., Chen, T. H., Wu, H., Rothenberg, E. V., and Sucov, H. M. (2001). A developmental transition in definitive erythropoiesis: erythropoietin expression is sequentially regulated by retinoic acid receptors and HNF4. Genes Dev. 15, 889-901. doi: 10.1101/gad.871601.
48. Masson, N., Singleton, R. S., Sekirnik, R., Trudgian, D. C., Ambrose, L. J., Miranda, M. X., et al. (2012). The FIH hydroxylase is a cellular peroxide sensor that modulates HIF transcriptional activity. EMBO Rep. 13, 251-257. doi: 10.1038/embor.2012.9.
49. Maxwell, P. H., Ferguson, D. J., Nicholls, L. G., Johnson, M. H., and Ratcliffe, P. J. (1997). The interstitial response to renal injury: fibroblast-like cells show phenotypic changes and have reduced potential for erythropoietin gene expression. Kidney Int. 52, 715-724. doi: 10.1038/ki.1997.387.
50. Maxwell, P. H., Osmond, M. K., Pugh, C. W., Heryet, A., Nicholls, L. G., Tan, C. C., et al. (1993). Identification of the renal erythropoietin-producing cells using transgenic mice. Kidney Int. 44, 1149-1162.
51. Miyake, T., Kung, C. K., and Goldwasser, E. (1977). Purification of human erythropoietin. J. Biol. Chem. 252, 5558-5564.
52. Miyata, T., Suzuki, N., and van Ypersele de Strihou, C. (2013). Diabetic nephropathy: are there new and potentially promising therapies targeting oxygen biology? Kidney Int. 84, 693-702. doi: 10.1038/ki.2013.74.
53. Nakano, Y., Imagawa, S., Matsumoto, K., Stockmann, C., Obara, N., Suzuki, N., et al. (2004). Oral administration of K-11706 inhibits GATA binding activity, enhances hypoxia-inducible factor 1 binding activity, and restores indicators in an in vivo mouse model of anemia of chronic disease. Blood 104, 4300-4307. doi: 10.1182/blood-2004-04-1631.
54. Nangaku, M. (2006). Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. J. Am. Soc. Nephrol. 17, 17-25. doi: 10.1681/ASN.2005070757.
55. Noguchi, C. T., Wang, L., Rogers, H. M., Teng, R., and Jia, Y. (2008). Survival and proliferative roles of erythropoietin beyond the erythroid lineage. Expert Rev. Mol. Med. 10:e36. doi: 10.1017/S1462399408000860.
56. Obara, N., Suzuki, N., Kim, K., Nagasawa, T., Imagawa, S., and Yamamoto, M. (2008). Repression via the GATA box is essential for tissue-specific erythropoietin gene expression. Blood 111, 5223-5232. doi: 10.1182/blood-2007-10-115857.
57. Pagel, H., Jelkmann, W., and Weiss, C. (1990). Erythropoietin production in the isolated perfused kidney. Biomed. Biochim. Acta. 49, S271-274.
58. Pan, X., Suzuki, N., Hirano, I., Yamazaki, S., Minegishi, N., and Yamamoto, M. (2011). Isolation and characterization of renal erythropoietin-producing cells from genetically produced anemia mice. PLoS ONE 6:e25839. doi: 10.1371/journal.pone.0025839.
59. Paragas, N., Qiu, A., Zhang, Q., Samstein, B., Deng, S. X., Schmidt-Ott, K. M., et al. (2011). The Ngal reporter mouse detects the response of the kidney to injury in real time. Nat. Med. 17, 216-222. doi: 10.1038/nm.2290.
60. Quaggin, S. E., and Kapus, A. (2011). Scar wars: mapping the fate of epithelial-mesenchymal-myofibroblast transition. Kidney Int. 80, 41-50. doi: 10.1038/ki.2011.77.
61. Rankin, E. B., Tomaszewski, J. E., and Haase, V. H. (2006). Renal cyst development in mice with conditional inactivation of the von Hippel-Lindau tumor suppressor. Cancer Res. 66, 2576-2583. doi: 10.1158/0008-5472.CAN-05-3241.
62. Ratcliffe, P. J. (2013). Oxygen sensing and hypoxia signalling pathways in animals: the implications of physiology for cancer. J. Physiol. 591, 2027-2042. doi: 10.1113/jphysiol.2013.251470.
63. Remy, I., Wilson, I. A., and Michnick, S. W. (1999). Erythropoietin receptor activation by a ligand-induced conformation change. Science 283, 990-993. doi: 10.1126/science.283.5404.990.
64. Roufosse, C., Bou-Gharios, G., Prodromidi, E., Alexakis, C., Jeffery, R., Khan, S., et al. (2006). Bone marrow-derived cells do not contribute significantly to collagen I synthesis in a murine model of renal fibrosis. J. Am. Soc. Nephrol. 17, 775-782. doi: 10.1681/ASN.2005080795.
65. Schrimpf, C., Xin, C., Campanholle, G., Gill, S. E., Stallcup, W., Lin, S. L., et al. (2012). Pericyte TIMP3 and ADAMTS1 modulate vascular stability after kidney injury. J. Am. Soc. Nephrol. 23, 868-883. doi: 10.1681/ASN.2011080851.
66. Schwartz, D. I., Pierratos, A., Richardson, R. M., Fenton, S. S., and Chan, C. T. (2005). Impact of nocturnal home hemodialysis on anemia management in patients with end-stage renal disease. Clin. Nephrol. 63, 202-208. doi: 10.5414/CNP63202.
67. Semenza, G. L. (2011). Oxygen sensing, homeostasis, and disease. N. Engl. J. Med. 365, 537-547. doi: 10.1056/NEJMra1011165.
68. Semenza, G. L., Koury, S. T., Nejfelt, M. K., Gearhart, J. D., and Antonarakis, S. E. (1991a). Cell-type-specific and hypoxia-inducible expression of the human erythropoietin gene in transgenic mice. Proc. Natl. Acad. Sci. U.S.A. 88, 8725-8729. doi: 10.1073/pnas.88.19.8725.
69. Semenza, G. L., Nejfelt, M. K., Chi, S. M., and Antonarakis, S. E. (1991b). Hypoxia-inducible nuclear factors bind to an enhancer element located 3' to the human erythropoietin gene. Proc. Natl. Acad. Sci. U.S.A. 88, 5680-5684. doi: 10.1073/pnas.88.13.5680.
70. Souma, T., Nezu, M., Nakano, D., Yamazaki, S., Hirano, I., Sekine, H., et al. (in press). Erythropoietin synthesis in renal myofibroblasts is restored by activation of hypoxia signaling. J. Am. Soc. Nephrol.
71. Souma, T., Yamazaki, S., Moriguchi, T., Suzuki, N., Hirano, I., Pan, X., et al. (2013). Plasticity of renal erythropoietin-producing cells governs fibrosis. J. Am. Soc. Nephrol. 24, 1599-1616. doi: 10.1681/ASN.2013010030.
72. Suzuki, N. (2015). Erythropoietin gene expression: developmental-stage specificity, cell-type specificity, and hypoxia inducibility. Tohoku J. Exp. Med. 235, 233-240. doi: 10.1620/tjem.235.233.
73. Suzuki, N., Hirano, I., Pan, X., Minegishi, N., and Yamamoto, M. (2013). Erythropoietin production in neuroepithelial and neural crest cells during primitive erythropoiesis. Nat. Commun. 4:2902. doi: 10.1038/ncomms3902.
74. Suzuki, N., Obara, N., Pan, X., Watanabe, M., Jishage, K., Minegishi, N., et al. (2011). Specific contribution of the erythropoietin gene 3' enhancer to hepatic erythropoiesis after late embryonic stages. Mol. Cell. Biol. 31, 3896-3905. doi: 10.1128/MCB.05463-11.
75. Suzuki, N., Obara, N., and Yamamoto, M. (2007). Use of gene-manipulated mice in the study of erythropoietin gene expression. Methods Enzymol. 435, 157-177. doi: 10.1016/S0076-6879(07)35009-X.
76. Suzuki, N., Suwabe, N., Ohneda, O., Obara, N., Imagawa, S., Pan, X., et al. (2003). Identification and characterization of 2 types of erythroid progenitors that express GATA-1 at distinct levels. Blood 102, 3575-3583. doi: 10.1182/blood-2003-04-1154.
77. Takeda, A., Toda, T., Shinohara, S., Mogi, Y., and Matsui, N. (2002). Factors contributing to higher hematocrit levels in hemodialysis patients not receiving recombinant human erythropoietin 1. Am. J. Kidney Dis. 40, 104-109. doi: 10.1053/ajkd.2002.33918.
78. Takeda, K., Aguila, H. L., Parikh, N. S., Li, X., Lamothe, K., Duan, L. J., et al. (2008). Regulation of adult erythropoiesis by prolyl hydroxylase domain proteins. Blood 111, 3229-3235. doi: 10.1182/blood-2007-09-114561.
79. Tanimoto, K., Makino, Y., Pereira, T., and Poellinger, L. (2000). Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein. EMBO J. 19, 4298-4309. doi: 10.1093/emboj/19.16.4298.
80. Tarumoto, T., Imagawa, S., Ohmine, K., Nagai, T., Higuchi, M., Imai, N., et al. (2000). N(G)-monomethyl-L-arginine inhibits erythropoietin gene expression by stimulating GATA-2. Blood 96, 1716-1722.
81. Tian, Y. M., Yeoh, K. K., Lee, M. K., Eriksson, T., Kessler, B. M., Kramer, H. B., et al. (2011). Differential sensitivity of hypoxia inducible factor hydroxylation sites to hypoxia and hydroxylase inhibitors. J. Biol. Chem. 286, 13041-13051. doi: 10.1074/jbc.M110.211110.
82. Wu, H., Liu, X., Jaenisch, R., and Lodish, H. F. (1995). Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor. Cell 83, 59-67. doi: 10.1016/0092-8674(95)90234-1.
83. Yamazaki, S., Souma, T., Hirano, I., Pan, X., Minegishi, N., Suzuki, N., et al. (2013). A mouse model of adult-onset anaemia due to erythropoietin deficiency. Nat. Commun. 4:1950. doi: 10.1038/ncomms2950.
84. Yin, H., and Blanchard, K. L. (2000). DNA methylation represses the expression of the human erythropoietin gene by two different mechanisms. Blood 95, 111-119.
85. Zeisberg, E. M., Potenta, S. E., Sugimoto, H., Zeisberg, M., and Kalluri, R. (2008). Fibroblasts in kidney fibrosis emerge via endothelial-to-mesenchymal transition. J. Am. Soc. Nephrol. 19, 2282-2287. doi: 10.1681/ASN.2008050513.
86. Zeisberg, M., Hanai, J., Sugimoto, H., Mammoto, T., Charytan, D., Strutz, F., et al. (2003). BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat. Med. 9, 964-968. doi: 10.1038/nm888.
87. Zhang, N., Fu, Z., Linke, S., Chicher, J., Gorman, J. J., Visk, D., et al. (2010). The asparaginyl hydroxylase factor inhibiting HIF-1alpha is an essential regulator of metabolism. Cell Metab. 11, 364-378. doi: 10.1016/j.cmet.2010.03.001.