Hypoxia-Inducible Factor Stabilizers: a New Avenue for Reducing BP While Helping Hemoglobin?
详细信息    查看全文
  • 作者:Farhanah Yousaf ; Bruce Spinowitz
  • 关键词:Hypoxia ; inducible factor ; HIF ; ; HIF ; 2 α ; Anemia ; Erythropoietin ; Iron ; Prolyl ; hydroxylase domain ; PHD inhibitors ; Hypertension ; Nitric oxide ; Pulmonary hypertension
  • 刊名:Current Hypertension Reports
  • 出版年:2016
  • 出版时间:March 2016
  • 年:2016
  • 卷:18
  • 期:3
  • 全文大小:559 KB
  • 参考文献:1.Babitt JL, Lin HY. Mechanisms of anemia in CKD. J Am Soc Nephrol. 2012;23(10):1631–4.PubMed PubMedCentral CrossRef
    2.Stivelman JC. Benefits of anaemia treatment on cognitive function. Nephrol Dial Transplant. 2000;15 Suppl 3:29–35.PubMed CrossRef
    3.Portolés J, López-Gómez JM, Aljama P. A prospective multicentre study of the role of anaemia as a risk factor in haemodialysis patients: the MAR Study. Nephrol Dial Transplant. 2007;22(2):500–7.PubMed CrossRef
    4.Ma JZ, Ebben J, Xia H, Collins AJ. Hematocrit level and associated mortality in hemodialysis patients. J Am Soc Nephrol. 1999 Mar;10(3):610–9.
    5.Karaboyas A, Zee J, Morgenstern H, Nolen JG, Hakim R, Kalantar-Zadeh K, et al. Understanding the recent increase in ferritin levels in United States dialysis patients: potential impact of changes in intravenous iron and erythropoiesis-stimulating agent dosing. Clin J Am Soc Nephrol. 2015;10(10):1814–21.PubMed CrossRef
    6.Revicki DA, Brown RE, Feeny DH, Henry D, Teehan BP, Rudnick MR, et al. Health-related quality of life associated with recombinant human erythropoietin therapy for predialysis chronic renal disease patients. Am J Kidney Dis. 1995;25(4):548–54.PubMed CrossRef
    7.United States Renal Data System, USRDS. 2012 Annual Data Report: atlas of chronic kidney and end-stage renal disease in the United States. Bethesda: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2012.
    8.McCullough PA, Barnhart HX, Inrig JK, Reddan D, Sapp S, Patel UD, et al. Cardiovascular toxicity of epoetin-alfa in patients with chronic kidney disease. Am J Nephrol. 2013;37(6):549–58.PubMed CrossRef
    9.Canadian Erythropoietin Study Group. Association between recombinant human erythropoietin and quality of life and exercise capacity of patients receiving haemodialysis. BMJ. 1990;300(6724):573–8.CrossRef
    10.Clyne N, Jogestrand T. Effect of erythropoietin treatment on physical exercise capacity and on renal function in predialytic uremic patients. Nephron. 1992;60(4):390–6.PubMed CrossRef
    11.Abraham PA, Opsahl JA, Keshaviah PR, Collins AJ, Whalen JJ, Asinger RW, et al. Body fluid spaces and blood pressure in hemodialysis patients during amelioration of anemia with erythropoietin. Am J Kidney Dis. 1990;16(5):438–46.PubMed CrossRef
    12.Bahlmann J, Schöter KH, Scigalla P, Gurland HJ, Hilfenhaus M, Koch KM, et al. Morbidity and mortality in hemodialysis patients with and without erythropoietin treatment: a controlled study. Contrib Nephrol. 1991;88:90–106.PubMed CrossRef
    13.Teehan BP, Benz RL, Sigler MH, Brown JM. Early intervention with recombinant human erythropoietin therapy. Semin Nephrol. 1990;10(2 Suppl 1):28–34.PubMed
    14.Bommer J, Müller-Bühl E, Ritz E, Eifert J. Recombinant human erythropoietin in anaemic patients on haemodialysis. Lancet. 1987;1(8529):392.PubMed CrossRef
    15.Bommer J, Alexiou C, Müller-Bühl U, Eifert J, Ritz E. Recombinant human erythropoietin therapy in haemodialysis patients—dose determination and clinical experience. Nephrol Dial Transplant. 1987;2(4):238–42.PubMed
    16.Casati S, Passerini P, Campise MR, Graziani G, Cesana B, Perisic M, et al. Benefits and risks of protracted treatment with human recombinant erythropoietin in patients having haemodialysis. Br Med J (Clin Res Ed). 1987;295(6605):1017–20.CrossRef
    17.Eschbach JW, Abdulhadi MH, Browne JK, Delano BG, Downing MR, Egrie JC, et al. Recombinant human erythropoietin in anemic patients with end-stage renal disease. Results of a phase III multicenter clinical trial. Ann Intern Med. 1989;111(12):992–1000.PubMed CrossRef
    18.Sundal E, Kaeser U. Correction of anaemia of chronic renal failure with recombinant human erythropoietin: safety and efficacy of one year’s treatment in a European multicentre study of 150 haemodialysis-dependent patients. Nephrol Dial Transplant. 1989;4(11):979–87.PubMed
    19.Samtleben W, Baldamus CA, Bommer J, Fassbinder W, Nonnast-Daniel B, Gurland HJ. Blood pressure changes during treatment with recombinant human erythropoietin. Contrib Nephrol. 1988;66:114–22.PubMed CrossRef
    20.Pollok M, Bommer J, Gurland HJ, Koch KM, Schoeppe W, Scigalla P, et al. Effects of recombinant human erythropoietin treatment in end-stage renal failure patients. Results of a multicenter phase II/III study. Contrib Nephrol. 1989;76:201–11. discussion 212-8.PubMed CrossRef
    21.Nonnast-Daniel B, Deschodt G, Brunkhorst R, Creutzig A, Bahlmann J, Shaldon S, et al. Long-term effects of treatment with recombinant human erythropoietin on haemodynamics and tissue oxygenation in patients with renal anaemia. Nephrol Dial Transplant. 1990;5(6):444–8.PubMed CrossRef
    22.Akizawa T, Koshikawa S, Takaku F, Urabe A, Akiyama N, Mimura N, et al. Clinical effect of recombinant human erythropoietin on anemia associated with chronic renal failure. A multi-institutional study in Japan. Int J Artif Organs. 1988;11(5):343–50.PubMed
    23.Baskin S, Lasker N. Erythropoietin-associated hypertension. N Engl J Med. 1990;323(14):999–1000.PubMed CrossRef
    24.Schaefer RM, Leschke M, Strauer BE, Heidland A. Blood rheology and hypertension in hemodialysis patients treated with erythropoietin. Am J Nephrol. 1988;8(6):449–53.PubMed CrossRef
    25.Strippoli GF, Craig JC, Manno C, Schena FP. Hemoglobin targets for the anemia of chronic kidney disease: a meta-analysis of randomized, controlled trials. J Am Soc Nephrol. 2004;15(12):3154–65.PubMed CrossRef
    26.Phrommintikul A, Haas SJ, Elsik M, Krum H. Mortality and target haemoglobin concentrations in anaemic patients with chronic kidney disease treated with erythropoietin: a meta-analysis. Lancet. 2007;369(9559):381–8.PubMed CrossRef
    27.Krapf R, Hulter HN. Arterial hypertension induced by erythropoietin and erythropoiesis-stimulating agents (ESA). Clin J Am Soc Nephrol. 2009;4(2):470–80.PubMed CrossRef
    28.Cody J, Daly C, Campbell M, Donaldson C, Khan I, Vale L, et al. Frequency of administration of recombinant human erythropoietin for anaemia of end-stage renal disease in dialysis patients. Cochrane Database Syst Rev. 2005;3, CD003895.PubMed
    29.Palmer SC, Saglimbene V, Mavridis D, Salanti G, Craig JC, Tonelli M, et al. Erythropoiesis-stimulating agents for anaemia in adults with chronic kidney disease: a network meta-analysis. Cochrane Database Syst Rev. 2014;12, CD010590.PubMed
    30.Annuk M, Linde T, Lind L, Fellström B. Erythropoietin impairs endothelial vasodilatory function in patients with renal anemia and in healthy subjects. Nephron Clin Pract. 2006;102(1):c30–4.PubMed CrossRef
    31.Kaupke CJ, Kim S, Vaziri ND. Effect of erythrocyte mass on arterial blood pressure in dialysis patients receiving maintenance erythropoietin therapy. J Am Soc Nephrol. 1994;4(11):1874–8.PubMed
    32.Kumar H, Choi DK. Hypoxia inducible factor pathway and physiological adaptation: a cell survival pathway? Mediat Inflamm. 2015;2015:584758.CrossRef
    33.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. 1992;12(12):5447–54.PubMed PubMedCentral CrossRef
    34.Hara S, Hamada J, Kobayashi C, Kondo Y, Imura N. Expression and characterization of hypoxia-inducible factor (HIF)-3alpha in human kidney: suppression of HIF-mediated gene expression by HIF-3alpha. Biochem Biophys Res Commun. 2001;287(4):808–13.PubMed CrossRef
    35.Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001;292(5516):468–72.PubMed CrossRef
    36.Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, et al. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001;292(5516):464–8.PubMed CrossRef
    37.Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999;399(6733):271–5.PubMed CrossRef
    38.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. 2002;16(12):1466–71.PubMed PubMedCentral CrossRef
    39.Hewitson KS, McNeill LA, Riordan MV, Tian YM, Bullock AN, Welford RW, et al. Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family. J Biol Chem. 2002;277(29):26351–5.PubMed CrossRef
    40.Lando D, Peet DJ, Whelan DA, Gorman JJ, Whitelaw ML. Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science. 2002;295(5556):858–61.PubMed CrossRef
    41.•
Greer SN, Metcalf JL, Wang Y, Ohh M. The updated biology of hypoxia-inducible factor. EMBO J. 2012;31(11):2448–60. Summarizes the regulation of HIF and relevant biological processes.PubMed PubMedCentral CrossRef
42.Choudhry H, Schödel J, Oikonomopoulos S, Camps C, Grampp S, Harris AL, et al. Extensive regulation of the non-coding transcriptome by hypoxia: role of HIF in releasing paused RNApol2. EMBO Rep. 2014;15(1):70–6.PubMed PubMedCentral CrossRef
43.•
Schödel J, Mole DR, Ratcliffe PJ. Pan-genomic binding of hypoxia-inducible transcription factors. Biol Chem. 2013;394(4):507–17. Reviews HIF binding sites that have been identified.PubMed CrossRef
44.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 U S A. 2007;104(7):2301–6.PubMed PubMedCentral CrossRef
45.Scortegagna M, Ding K, Zhang Q, Oktay Y, Bennett MJ, Bennett M, et al. HIF-2alpha regulates murine hematopoietic development in an erythropoietin-dependent manner. Blood. 2005;105(8):3133–40.PubMed CrossRef
46.Paliege A, Rosenberger C, Bondke A, Sciesielski L, Shina A, Heyman SN, et al. Hypoxia-inducible factor-2alpha-expressing interstitial fibroblasts are the only renal cells that express erythropoietin under hypoxia-inducible factor stabilization. Kidney Int. 2010;77(4):312–8.PubMed CrossRef
47.Furlow PW, Percy MJ, Sutherland S, Bierl C, McMullin MF, Master SR, et al. Erythrocytosis-associated HIF-2alpha mutations demonstrate a critical role for residues C-terminal to the hydroxylacceptor proline. J Biol Chem. 2009;284(14):9050–8.PubMed PubMedCentral CrossRef
48.Martini M, Teofili L, Cenci T, Giona F, Torti L, Rea M, et al. A novel heterozygous HIF2AM535I mutation reinforces the role of oxygen sensing pathway disturbances in the pathogenesis of familial erythrocytosis. Haematologica. 2008;93(7):1068–71.PubMed CrossRef
49.Simpson RJ, McKie AT. Iron and oxygen sensing: a tale of 2 interacting elements? Metallomics. 2015;7(2):223–31.PubMed CrossRef
50.van Wijk R, Sutherland S, Van Wesel AC, Huizinga EG, Percy MJ, Bierings M, et al. Erythrocytosis associated with a novel missense mutation in the HIF2A gene. Haematologica. 2010;95(5):829–32.PubMed PubMedCentral CrossRef
51.Bosch-Marce M, Okuyama H, Wesley JB, Sarkar K, Kimura H, Liu YV, et al. Effects of aging and hypoxia-inducible factor-1 activity on angiogenic cell mobilization and recovery of perfusion after limb ischemia. Circ Res. 2007;101(12):1310–8.PubMed CrossRef
52.Wheaton WW, Chandel NS. Hypoxia. 2. Hypoxia regulates cellular metabolism. Am J Physiol Cell Physiol. 2011;300(3):C385–93.PubMed PubMedCentral CrossRef
53.Berra E, Benizri E, Ginouvès A, Volmat V, Roux D, Pouysségur J. HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia. EMBO J. 2003;22(16):4082–90.PubMed PubMedCentral CrossRef
54.Appelhoff RJ, Tian YM, Raval RR, Turley H, Harris AL, Pugh CW, et al. Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. J Biol Chem. 2004;279(37):38458–65.PubMed CrossRef
55.Takeda K, Aguila HL, Parikh NS, Li X, Lamothe K, Duan LJ, et al. Regulation of adult erythropoiesis by prolyl hydroxylase domain proteins. Blood. 2008;111(6):3229–35.PubMed PubMedCentral CrossRef
56.Laitala A, Aro E, Walkinshaw G, Mäki JM, Rossi M, Heikkilä M, et al. Transmembrane prolyl 4-hydroxylase is a fourth prolyl 4-hydroxylase regulating EPO production and erythropoiesis. Blood. 2012;120(16):3336–44.PubMed CrossRef
57.Minamishima YA, Kaelin Jr WG. Reactivation of hepatic EPO synthesis in mice after PHD loss. Science. 2010;329(5990):407.PubMed PubMedCentral CrossRef
58.Bishop T, Gallagher D, Pascual A, Lygate CA, de Bono JP, Nicholls LG, et al. Abnormal sympathoadrenal development and systemic hypotension in PHD3-/- mice. Mol Cell Biol. 2008;28(10):3386–400.PubMed PubMedCentral CrossRef
59.Sato Y, Yanagita M. Renal anemia: from incurable to curable. Am J Physiol Renal Physiol. 2013;305(9):F1239–48.PubMed CrossRef
60.Nagai T, Yasuoka Y, Izumi Y, Horikawa K, Kimura M, Nakayama Y, et al. Reevaluation of erythropoietin production by the nephron. Biochem Biophys Res Commun. 2014;449(2):222–8.PubMed CrossRef
61.•
Gerl K, Miquerol L, Todorov VT, Hugo CP, Adams RH, Kurtz A, et al. Inducible glomerular erythropoietin production in the adult kidney. Kidney Int. 2015;88(6):1345–55. Describes other renal cells that can be induced to express EPO.PubMed CrossRef
62.Kurt B, Paliege A, Willam C, Schwarzensteiner I, Schucht K, Neymeyer H, et al. Deletion of von Hippel-Lindau protein converts renin-producing cells into erythropoietin-producing cells. J Am Soc Nephrol. 2013;24(3):433–44.PubMed PubMedCentral CrossRef
63.Kurt B, Gerl K, Karger C, Schwarzensteiner I, Kurtz A. Chronic hypoxia-inducible transcription factor-2 activation stably transforms juxtaglomerular renin cells into fibroblast-like cells in vivo. J Am Soc Nephrol. 2015;26(3):587–96.PubMed PubMedCentral CrossRef
64.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. 2006;291(4):F902–12.PubMed CrossRef
65.Rankin EB, Biju MP, Liu Q, Unger TL, Rha J, Johnson RS, et al. Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo. J Clin Invest. 2007;117(4):1068–77.PubMed PubMedCentral CrossRef
66.Bernaudin M, Bellail A, Marti HH, Yvon A, Vivien D, Duchatelle I, et al. Neurons and astrocytes express EPO mRNA: oxygen-sensing mechanisms that involve the redox-state of the brain. Glia. 2000;30(3):271–8.PubMed CrossRef
67.Weidemann A, Kerdiles YM, Knaup KX, Rafie CA, Boutin AT, Stockmann C, et al. The glial cell response is an essential component of hypoxia-induced erythropoiesis in mice. J Clin Invest. 2009;119(11):3373–83.PubMed PubMedCentral
68.Rankin EB, Wu C, Khatri R, Wilson TL, Andersen R, Araldi E, et al. The HIF signaling pathway in osteoblasts directly modulates erythropoiesis through the production of EPO. Cell. 2012;149(1):63–74.PubMed PubMedCentral CrossRef
69.Chiang CK, Tanaka T, Inagi R, Fujita T, Nangaku M. Indoxyl sulfate, a representative uremic toxin, suppresses erythropoietin production in a HIF-dependent manner. Lab Investig. 2011;91(11):1564–71.PubMed CrossRef
70.Pasqualetti P, Casale R. Circadian rhythm of serum erythropoietin in healthy subjects. Riv Eur Sci Med Farmacol. 1996;18(3):91–3.PubMed
71.Egg M, Köblitz L, Hirayama J, Schwerte T, Folterbauer C, Kurz A, et al. Linking oxygen to time: the bidirectional interaction between the hypoxic signaling pathway and the circadian clock. Chronobiol Int. 2013;30(4):510–29.PubMed CrossRef
72.Jelkmann W. Erythropoietin: structure, control of production, and function. Physiol Rev. 1992;72(2):449–89.PubMed
73.•
Brines M. The therapeutic potential of erythropoiesis-stimulating agents for tissue protection: a tale of two receptors. Blood Purif. 2010;29(2):86–92. Reviews the two types of EPO receptors and their implications.PubMed CrossRef
74.Garimella PS, Katz R, Patel KV, Kritchevsky SB, Parikh CR, Ix JH, et al. Association of serum erythropoietin with cardiovascular events, kidney function decline, and mortality: the Health Aging and Body Composition Study. Circ Heart Fail. 2016;9(1):e002124.PubMed CrossRef
75.Kanbay M, Perazella MA, Kasapoglu B, Koroglu M, Covic A. Erythropoiesis stimulatory agent- resistant anemia in dialysis patients: review of causes and management. Blood Purif. 2010;29(1):1–12.PubMed CrossRef
76.Johnson DW, Pollock CA, Macdougall IC. Erythropoiesis-stimulating agent hyporesponsiveness. Nephrology (Carlton). 2007;12(4):321–30.CrossRef
77.Ganz T. Hepcidin and the global burden of iron deficiency. Clin Chem. 2015;61(4):577–8.PubMed CrossRef
78.Nemeth E, Ganz T. The role of hepcidin in iron metabolism. Acta Haematol. 2009;122(2-3):78–86.PubMed PubMedCentral CrossRef
79.•Ganz T. Systemic iron homeostasis. Physiol Rev. 2013;93(4):1721–41. Summarizes the regulation of iron and the elements involved.PubMed CrossRef
80.Rishi G, Wallace DF, Subramaniam VN. Hepcidin: regulation of the master iron regulator. Biosci Rep. 2015;35(3). pii: e00192.
81.Nicolas G, Chauvet C, Viatte L, Danan JL, Bigard X, Devaux I, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest. 2002;110(7):1037–44.PubMed PubMedCentral CrossRef
82.Camaschella C. Iron and hepcidin: a story of recycling and balance. Hematol Am Soc Hematol Educ Program. 2013;2013:1–8.CrossRef
83.Peyssonnaux C, Zinkernagel AS, Schuepbach RA, Rankin E, Vaulont S, Haase VH, et al. Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J Clin Invest. 2007;117(7):1926–32.PubMed PubMedCentral CrossRef
84.Volke M, Gale DP, Maegdefrau U, Schley G, Klanke B, Bosserhoff AK, et al. Evidence for a lack of a direct transcriptional suppression of the iron regulatory peptide hepcidin by hypoxia-inducible factors. PLoS One. 2009;4(11):e7875.PubMed PubMedCentral CrossRef
85.Mastrogiannaki M, Matak P, Mathieu JR, Delga S, Mayeux P, Vaulont S, et al. Hepatic hypoxia-inducible factor-2 down-regulates hepcidin expression in mice through an erythropoietin-mediated increase in erythropoiesis. Haematologica. 2012;97(6):827–34.PubMed PubMedCentral CrossRef
86.Anderson ER, Xue X, Shah YM. Intestinal hypoxia-inducible factor-2alpha (HIF-2alpha) is critical for efficient erythropoiesis. J Biol Chem. 2011;286(22):19533–40.PubMed PubMedCentral CrossRef
87.Taylor M, Qu A, Anderson ER, Matsubara T, Martin A, Gonzalez FJ, et al. Hypoxia-inducible factor-2α mediates the adaptive increase of intestinal ferroportin during iron deficiency in mice. Gastroenterology. 2011;140(7):2044–55.PubMed PubMedCentral CrossRef
88.Mastrogiannaki M, Matak P, Delga S, Deschemin JC, Vaulont S, Peyssonnaux C. Deletion of HIF-2α in the enterocytes decreases the severity of tissue iron loading in hepcidin knockout mice. Blood. 2012;119(2):587–90.PubMed CrossRef
89.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. 2009;119(5):1159–66.PubMed PubMedCentral CrossRef
90.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. 2009;9(2):152–64.PubMed PubMedCentral CrossRef
91.Rolfs A, Kvietikova I, Gassmann M, Wenger RH. Oxygen-regulated transferrin expression is mediated by hypoxia-inducible factor-1. J Biol Chem. 1997;272(32):20055–62.PubMed CrossRef
92.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. 1999;274(34):24142–6.PubMed CrossRef
93.Mukhopadhyay CK, Mazumder B, Fox PL. Role of hypoxia-inducible factor-1 in transcriptional activation of ceruloplasmin by iron deficiency. J Biol Chem. 2000;275(28):21048–54.PubMed CrossRef
94.Silvestri L, Pagani A, Camaschella C. Furin-mediated release of soluble hemojuvelin: a new link between hypoxia and iron homeostasis. Blood. 2008;111(2):924–31.PubMed CrossRef
95.Lee PJ, Jiang BH, Chin BY, Iyer NV, Alam J, Semenza GL, et al. Hypoxia-inducible factor-1 mediates transcriptional activation of the heme oxygenase-1 gene in response to hypoxia. J Biol Chem. 1997;272(9):5375–81.PubMed CrossRef
96.Mathieu JR, Heinis M, Zumerle S, Delga S, Le Bon A, Peyssonnaux C. Investigating the real role of HIF-1 and HIF-2 in iron recycling by macrophages. Haematologica. 2014;99(7):e112–4.PubMed PubMedCentral CrossRef
97.Ashby DR, Gale DP, Busbridge M, Murphy KG, Duncan ND, Cairns TD, et al. Plasma hepcidin levels are elevated but responsive to erythropoietin therapy in renal disease. Kidney Int. 2009;75(9):976–81.PubMed CrossRef
98.Kitsati N, Liakos D, Ermeidi E, Mantzaris MD, Vasakos S, Kyratzopoulou E, et al. Rapid elevation of transferrin saturation and serum hepcidin concentration in hemodialysis patients after intravenous iron infusion. Haematologica. 2015;100(3):e80–3.PubMed PubMedCentral CrossRef
99.Kuragano T, Itoh K, Shimonaka Y, Kida A, Furuta M, Kitamura R, et al. Hepcidin as well as TNF-α are significant predictors of arterial stiffness in patients on maintenance hemodialysis. Nephrol Dial Transplant. 2011;26(8):2663–7.PubMed CrossRef
100.Kali A, Yayar O, Erdogan B, Eser B, Buyukbakkal M, Ercan Z, Merhametsiz O, Haspulat A, Gök Oğuz E, Canbakan B, Ayli MD. Is hepcidin-25 a predictor of atherosclerosis in hemodialysis patients? Hemodial Int. 2015. doi:10.​1111/​hdi.​12355 .
101.van der Weerd NC, Grooteman MP, Bots ML, van den Dorpel MA, den Hoedt CH, Mazairac AH, et al. Hepcidin-25 is related to cardiovascular events in chronic haemodialysis patients. Nephrol Dial Transplant. 2013;28(12):3062–71.PubMed CrossRef
102.Suárez-Ortegón MF, Arbeláez A, Mosquera M, Moreno-Navarrete JM, Aguilar-Plata C, Fernández-Real JM. Circulating hepcidin is independently associated with systolic blood pressure in apparently healthy individuals. Arch Med Res. 2015;46(6):507–13.PubMed CrossRef
103.Galesloot TE, Holewijn S, Kiemeney LA, de Graaf J, Vermeulen SH, Swinkels DW. Serum hepcidin is associated with presence of plaque in postmenopausal women of a general population. Arterioscler Thromb Vasc Biol. 2014;34(2):446–56.PubMed CrossRef
104.Valenti L, Maloberti A, Signorini S, Milano M, Cesana F, Cappellini F, et al. Iron stores, hepcidin, and aortic stiffness in individuals with hypertension. PLoS One. 2015;10(8), e0134635.PubMed PubMedCentral CrossRef
105.Akhtar S, Hartmann P, Karshovska E, Rinderknecht FA, Subramanian P, Gremse F, et al. Endothelial hypoxia-inducible factor-1α promotes atherosclerosis and monocyte recruitment by upregulating microRNA-19a. Hypertension. 2015;66(6):1220–6.PubMed
106.Wagner M, Ashby DR, Kurtz C, Alam A, Busbridge M, Raff U, et al. Hepcidin-25 in diabetic chronic kidney disease is predictive for mortality and progression to end stage renal disease. PLoS One. 2015;10(4), e0123072.PubMed PubMedCentral CrossRef
107.Masoud GN, Li W. HIF-1α pathway: role, regulation and intervention for cancer therapy. Acta Pharm Sin B. 2015;5(5):378–89.PubMed PubMedCentral CrossRef
108.•Goel HL, Mercurio AM. VEGF targets the tumour cell. Nat Rev Cancer. 2013;13(12):871–82. Discusses the role of VEGF in tumor biology.PubMed PubMedCentral CrossRef
109.Miller JW, Le Couter J, Strauss EC, Ferrara N. Vascular endothelial growth factor a in intraocular vascular disease. Ophthalmology. 2013;120(1):106–14.PubMed CrossRef
110.Watson CJ, Collier P, Tea I, Neary R, Watson JA, Robinson C, et al. Hypoxia-induced epigenetic modifications are associated with cardiac tissue fibrosis and the development of a myofibroblast-like phenotype. Hum Mol Genet. 2014;23(8):2176–88.PubMed CrossRef
111.Sui X, Wei H, Wang D. Novel mechanism of cardiac protection by valsartan: synergetic roles of TGF-β1 and HIF-1α in Ang II-mediated fibrosis after myocardial infarction. J Cell Mol Med. 2015;19(8):1773–82.PubMed PubMedCentral CrossRef
112.Zhan L, Huang C, Meng XM, Song Y, Wu XQ, Yang Y, et al. Hypoxia-inducible factor-1alpha in hepatic fibrosis: a promising therapeutic target. Biochimie. 2015;108:1–7.PubMed CrossRef
113.Wang Z, Zhu Q, Li PL, Dhaduk R, Zhang F, Gehr TW, et al. Silencing of hypoxia-inducible factor-1α gene attenuates chronic ischemic renal injury in two-kidney, one-clip rats. Am J Physiol Renal Physiol. 2014;306(10):F1236–42.PubMed PubMedCentral CrossRef
114.Kapitsinou PP, Sano H, Michael M, Kobayashi H, Davidoff O, Bian A, et al. Endothelial HIF-2 mediates protection and recovery from ischemic kidney injury. J Clin Invest. 2014;124(6):2396–409.PubMed PubMedCentral CrossRef
115.Zhang S, Ma K, Liu Y, Pan X, Chen Q, Qi L, Li S. Stabilization of Hypoxia Inducible Factor by DMOG Inhibits Development of Chronic Hypoxia-Induced Right Ventricular Remodeling. J Cardiovasc Pharmacol. 2015.
116.Kido M, Du L, Sullivan CC, Li X, Deutsch R, Jamieson SW, et al. Hypoxia-inducible factor 1-alpha reduces infarction and attenuates progression of cardiac dysfunction after myocardial infarction in the mouse. J Am Coll Cardiol. 2005;46(11):2116–24.PubMed CrossRef
117.Lokmic Z, Musyoka J, Hewitson TD, Darby IA. Hypoxia and hypoxia signaling in tissue repair and fibrosis. Int Rev Cell Mol Biol. 2012;296:139–85.PubMed CrossRef
118.Shao J, Zhang Y, Yang T, Qi J, Zhang L, Deng L. HIF-1α disturbs osteoblasts and osteoclasts coupling in bone remodeling by up-regulating OPG expression. In Vitro Cell Dev Biol Anim. 2015;51(8):808–14.PubMed CrossRef
119.Wu C, Rankin EB, Castellini L, Alcudia JF, LaGory EL, Andersen R, et al. Corrigendum: oxygen-sensing PHDs regulate bone homeostasis through the modulation of osteoprotegerin. Genes Dev. 2015;29(11):1202.PubMed PubMedCentral
120.Knowles HJ, Cleton-Jansen AM, Korsching E, Athanasou NA. Hypoxia-inducible factor regulates osteoclast-mediated bone resorption: role of angiopoietin-like 4. FASEB J. 2010;24(12):4648–59.PubMed PubMedCentral CrossRef
121.Shirakura M, Tanimoto K, Eguchi H, Miyauchi M, Nakamura H, Hiyama K, et al. Activation of the hypoxia-inducible factor-1 in overloaded temporomandibular joint, and induction of osteoclastogenesis. Biochem Biophys Res Commun. 2010;393(4):800–5.PubMed CrossRef
122.Miyauchi Y, Sato Y, Kobayashi T, Yoshida S, Mori T, Kanagawa H, et al. HIF1α is required for osteoclast activation by estrogen deficiency in postmenopausal osteoporosis. Proc Natl Acad Sci U S A. 2013;110(41):16568–73.PubMed PubMedCentral CrossRef
123.Formenti F, Beer PA, Croft QP, Dorrington KL, Gale DP, Lappin TR, et al. Cardiopulmonary function in two human disorders of the hypoxia-inducible factor (HIF) pathway: von Hippel–Lindau disease and HIF-2alpha gain-of-function mutation. FASEB J. 2011;25(6):2001–11.PubMed PubMedCentral CrossRef
124.Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, et al. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev. 1998;12(2):149–62.PubMed PubMedCentral CrossRef
125.Yu AY, Shimoda LA, Iyer NV, Huso DL, Sun X, McWilliams R, et al. Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1alpha. J Clin Invest. 1999;103(5):691–6.PubMed PubMedCentral CrossRef
126.Galié N, Manes A, Branzi A. The endothelin system in pulmonary arterial hypertension. Cardiovasc Res. 2004;61(2):227–37.PubMed CrossRef
127.Li H, Chen SJ, Chen YF, Meng QC, Durand J, Oparil S, et al. Enhanced endothelin-1 and endothelin receptor gene expression in chronic hypoxia. J Appl Physiol (1985). 1994;77(3):1451–9.
128.Shimoda LA, Sham JS, Liu Q, Sylvester JT. Acute and chronic hypoxic pulmonary vasoconstriction: a central role for endothelin-1? Respir Physiol Neurobiol. 2002;132(1):93–106.PubMed CrossRef
129.Li M, Liu Y, Jin F, Sun X, Li Z, Liu Y, et al. Endothelin-1 induces hypoxia inducible factor 1α expression in pulmonary artery smooth muscle cells. FEBS Lett. 2012;586(21):3888–93.PubMed CrossRef
130.Pisarcik S, Maylor J, Lu W, Yun X, Undem C, Sylvester JT, et al. Activation of hypoxia-inducible factor-1 in pulmonary arterial smooth muscle cells by endothelin-1. Am J Physiol Lung Cell Mol Physiol. 2013;304(8):L549–61.PubMed PubMedCentral CrossRef
131.Gale DP, Harten SK, Reid CD, Tuddenham EG, Maxwell PH. Autosomal dominant erythrocytosis and pulmonary arterial hypertension associated with an activating HIF2 alpha mutation. Blood. 2008;112(3):919–21.PubMed CrossRef
132.Tan Q, Kerestes H, Percy MJ, Pietrofesa R, Chen L, Khurana TS, et al. Erythrocytosis and pulmonary hypertension in a mouse model of human HIF2A gain of function mutation. J Biol Chem. 2013;288(24):17134–44.PubMed PubMedCentral CrossRef
133.Bushuev VI, Miasnikova GY, Sergueeva AI, Polyakova LA, Okhotin D, Gaskin PR, et al. Endothelin-1, vascular endothelial growth factor and systolic pulmonary artery pressure in patients with Chuvash polycythemia. Haematologica. 2006;91(6):744–9.PubMed
134.Hickey MM, Richardson T, Wang T, Mosqueira M, Arguiri E, Yu H, et al. The von Hippel-Lindau Chuvash mutation promotes pulmonary hypertension and fibrosis in mice. J Clin Invest. 2010;120(3):827–39.PubMed PubMedCentral CrossRef
135.Shimoda LA, Laurie SS. HIF and pulmonary vascular responses to hypoxia. J Appl Physiol (1985). 2014;116(7):867–74.CrossRef
136.Schofield CJ, Ratcliffe PJ. Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol. 2004;5(5):343–54.PubMed CrossRef
137.Garcia-Morales LJ, Chen NY, Weng T, Luo F, Davies J, Philip K, Volcik KA, Melicoff E, Amione-Guerra J, Bunge RR, Bruckner BA, Loebe M, Eltzschig HK, Pandit LM, Blackburn MR, Karmouty-Quintana H. Altered hypoxic-adenosine axis and metabolism in group III pulmonary hypertension. Am J Respir Cell Mol Biol. 2015 (in press).
138.Bernhardt WM, Wiesener MS, Scigalla P, Chou J, Schmieder RE, Günzler V, et al. Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD. J Am Soc Nephrol. 2010;21(12):2151–6.PubMed PubMedCentral CrossRef
139.Besarab A, Provenzano R, Hertel J, Zabaneh R, Klaus SJ, Lee T, et al. Randomized placebo-controlled dose-ranging and pharmacodynamics study of roxadustat (FG-4592) to treat anemia in nondialysis-dependent chronic kidney disease (NDD-CKD) patients. Nephrol Dial Transplant. 2015;30(10):1665–73.PubMed PubMedCentral CrossRef
140.Besarab A, Provenzano R, Fishbane S, Sun CH, Belo DS, Neff TB, et al. FG-4592 oral hypoxia-inducible factor prolyl hydroxylase inhibitor corrects anemia in nondialysis CKD patients without IV iron [abstract]. J Am Soc Nephrol. 2011;22:196A.
141.Besarab A, Chernyavskaya E, Motylev I, Shutov E, Kumbar LM, Gurevich K, Chan DT, Leong R, Poole L, Zhong M, Saikali KG, Franco M, Hemmerich S, Yu KP, Neff TB. Roxadustat (FG-4592): Correction of anemia in incident dialysis patients. J Am Soc Nephrol. 2015 (in press).
142.Szczech L, Besarab A, Saikali KG, Hemmerich A, Roberts BK, Poole L, et al. Anemia correction with roxadustat lowers hepcidin in chronic kidney disease (CKD) patients [abstract]. J Am Soc Nephrol. 2015;26:237A.CrossRef
143.Besarab A, Szczech L, Yu KHP, Neff TB. Impact of iron regimen on iron indices and hepcidin during roxadustat anemia correction in incident dialysis patients [abstract]. J Am Soc Nephrol. 2014;25:304A.
144.Szczech L, Besarab A, Saikali KG, Hemmerich S, Roberts BK, Poole L, et al. Anemia correction with roxadustat increases soluble transferrin receptor (sTfR) in chronic kidney disease (CKD) patients [abstract]. J Am Soc Nephrol. 2015;26:237A.CrossRef
145.Szczech L, Besarab A, Saikali KG, Hemmerich S, Roberts BK, Poole L, et al. Anemia correction with roxadustat lowers cholesterol in chronic kidney disease (CKD) patients [abstract]. J Am Soc Nephrol. 2015;26:237A.CrossRef
146.Szczech L, Hemmerich S, Besarab A, Saikali KG, Poole L, Yu KHP, et al. Anemia correction with roxadustat improves health related quality of life (HRQOL) in chronic kidney disease (CKD) patients [abstract]. J Am Soc Nephrol. 2015;26:11A.CrossRef
147.Holdstock L, Meadowcroft AM, Maier R, Johnson BM, Jones D, Rastogi A, et al. Four-week studies of oral hypoxia-inducible factor-prolyl hydroxylase inhibitor GSK1278863 for treatment of anemia. J Am Soc Nephrol. 2015;22.
148.Hartman CS, Smith MT, Flinn C, Shalwitz I, Peters KG, Shalwitz RA, et al. AKB-6548, a new hypoxia-inducible factor prolyl hydroxylase inhibitor increases hemoglobin while decreasing ferritin in a 28-day, phase 2a dose escalation study in stage 3 and 4 chronic kidney disease patients with anemia[abstract]. Poster session presented at: Kidney Week 2011. Philadelphia: American Society of Nephrology; 2011.
149.Hartman CS, Shalwitz I, Shalwitz RA. Controlled hemoglobin response in a double-blind, placebo-controlled trial of AKB-6548 in subjects with chronic kidney disease [abstract]. Oral session presented at: 51st ERA-EDTA Congress. European Renal Association—European Dialysis and Transplant Association; 2014 May 31-Jun 3; Amsterdam, The Netherlands. PowerPoint slides retrieved from: [http://​akebia.​com/​media/​publications/​ ]. Accessed 2015 Nov 25.
150.Haase VH, Spinowitz BS, Pergola PE, Farmer T, Maroni BJ, Hartman CS. AKB-6548 demonstrates controlled hemoglobin (HGB) response in a phase 2b study for the treatment of anemia in patients with chronic kidney disease not on dialysis (ND-CKD) [abstract]. J Am Soc Nephrol. 2015;26:237A.CrossRef
151.Buch A, Maroni BJ, Hartman CS. Dose exposure relationship of vadadustat is independent of the level of renal function [abstract]. Poster session presented at: Kidney Week 2015. San Diego: American Society of Nephrology; 2015.
152.Haase VH, Hartman CS, Maroni BJ, Farzaneh-Far R, McCullough PA. Vadadustat, a novel oral treatment for anemia of chronic kidney disease, maintains stable hemoglobin levels in dialysis patients converting from erythropoiesis-stimulating agents [abstract]. Poster session presented at: Kidney Week 2015. San Diego: American Society of Nephrology; 2015.
153.Shalwitz RA. AKB-6548, a novel hypoxia-inducible factor prolyl hydroxylase inhibitor reduces hepcidin and ferritin while it increases reticulocyte production and total iron binding capacity in healthy adults [abstract]. Poster session presented at: Kidney Week 2011. Philadelphia: American Society of Nephrology; 2011.
154.Flamme I, Oehme F, Ellinghaus P, Jeske M, Keldenich J, Thuss U. Mimicking hypoxia to treat anemia: HIF-stabilizer BAY 85-3934 (Molidustat) stimulates erythropoietin production without hypertensive effects. PLoS One. 2014;9(11), e111838.PubMed PubMedCentral CrossRef
155.Boettcher MF, Lentini S, Kaiser A, Flamme I, Kubitza D, Wensing G. First-in-man study with BAY 85-3934—a new oral selective HIF-PH inhibitor for the treatment of renal anemia [abstract]. J Am Soc Nephrol. 2013;24:347A.
156.Yoon D, Okhotin DV, Kim B, Okhotina Y, Okhotin DJ, Miasnikova GY, et al. Increased size of solid organs in patients with Chuvash polycythemia and in mice with altered expression of HIF-1alpha and HIF-2alpha. J Mol Med (Berl). 2010;88(5):523–30.CrossRef
157.Hermann M, Flammer A, Lüscher TF. Nitric oxide in hypertension. J Clin Hypertens (Greenwich). 2006;8(12 Suppl 4):17–29.CrossRef
158.Ghasemi A, Zahediasl S, Syedmoradi L, Azizi F. Association between serum nitric oxide metabolites and hypertension in a general population. Int Angiol. 2011;30(4):380–7.PubMed
159.Dong JY, Qin LQ, Zhang Z, Zhao Y, Wang J, Arigoni F, et al. Effect of oral L-arginine supplementation on blood pressure: a meta-analysis of randomized, double-blind, placebo-controlled trials. Am Heart J. 2011;162(6):959–65.PubMed CrossRef
160.Gokce N. L-arginine and hypertension. J Nutr. 2004;134(10 Suppl):2807S–11. discussion 2818S-2819S.PubMed
161.•Cowburn AS, Takeda N, Boutin AT, Kim JW, Sterling JC, Nakasaki M, et al. HIF isoforms in the skin differentially regulate systemic arterial pressure. Proc Natl Acad Sci U S A. 2013;110(43):17570–5. Highlights the significance of the balance of HIF isoforms in the regulation of blood pressure.PubMed PubMedCentral CrossRef
162.Takeda N, O’Dea EL, Doedens A, Kim JW, Weidemann A, Stockmann C, et al. Differential activation and antagonistic function of HIF-{alpha} isoforms in macrophages are essential for NO homeostasis. Genes Dev. 2010;24(5):491–501.PubMed PubMedCentral CrossRef
163.Nagai M, Terao S, Vital SA, Rodrigues SF, Yilmaz G, Granger DN. Role of blood cell-associated angiotensin II type 1 receptors in the cerebral microvascular response to ischemic stroke during angiotensin-induced hypertension. Exp Transl Stroke Med. 2011;3:15.PubMed PubMedCentral CrossRef
164.Munder M, Eichmann K, Modolell M. Alternative metabolic states in murine macrophages reflected by the nitric oxide synthase/arginase balance: competitive regulation by CD4+ T cells correlates with Th1/Th2 phenotype. J Immunol. 1998;160(11):5347–54.PubMed
165.Melillo G, Musso T, Sica A, Taylor LS, Cox GW, Varesio L. A hypoxia-responsive element mediates a novel pathway of activation of the inducible nitric oxide synthase promoter. J Exp Med. 1995;182(6):1683–93.PubMed CrossRef
166.Sogawa K, Numayama-Tsuruta K, Ema M, Abe M, Abe H, Fujii-Kuriyama Y. Inhibition of hypoxia-inducible factor 1 activity by nitric oxide donors in hypoxia. Proc Natl Acad Sci U S A. 1998;95(13):7368–73.PubMed PubMedCentral CrossRef
167.Chowdhury R, Godoy LC, Thiantanawat A, Trudel LJ, Deen WM, Wogan GN. Nitric oxide produced endogenously is responsible for hypoxia-induced HIF-1α stabilization in colon carcinoma cells. Chem Res Toxicol. 2012;25(10):2194–202.PubMed PubMedCentral CrossRef
168.Palmer LA, Gaston B, Johns RA. Normoxic stabilization of hypoxia-inducible factor-1 expression and activity: redox-dependent effect of nitrogen oxides. Mol Pharmacol. 2000;58(6):1197–203.PubMed
169.Metzen E, Zhou J, Jelkmann W, Fandrey J, Brüne B. Nitric oxide impairs normoxic degradation of HIF-1alpha by inhibition of prolyl hydroxylases. Mol Biol Cell. 2003;14(8):3470–81.PubMed PubMedCentral CrossRef
170.Yuan G, Peng YJ, Reddy VD, Makarenko VV, Nanduri J, Khan SA, et al. Mutual antagonism between hypoxia-inducible factors 1α and 2α regulates oxygen sensing and cardio-respiratory homeostasis. Proc Natl Acad Sci U S A. 2013;110(19):E1788–96.PubMed PubMedCentral CrossRef
171.•Nanduri J, Peng YJ, Yuan G, Kumar GK, Prabhakar NR. Hypoxia-inducible factors and hypertension: lessons from sleep apnea syndrome. J Mol Med (Berl). 2015;93(5):473–80. Reviews the implications of HIF axis in the development of chronic intermittent hypoxia related hypertension.CrossRef
172.Luo R, Zhang W, Zhao C, Zhang Y, Wu H, Jin J, et al. Elevated endothelial hypoxia-inducible factor-1α contributes to glomerular injury and promotes hypertensive chronic kidney disease. Hypertension. 2015;66(1):75–84.PubMed CrossRef
173.Weinberger MH, Miller JZ, Luft FC, Grim CE, Fineberg NS. Definitions and characteristics of sodium sensitivity and blood pressure resistance. Hypertension. 1986;8(6 Pt 2):II127–34.PubMed
174.Weinberger MH, Fineberg NS, Fineberg SE, Weinberger M. Salt sensitivity, pulse pressure, and death in normal and hypertensive humans. Hypertension. 2001;37(2 Pt 2):429–32.PubMed CrossRef
175.Campese VM. Salt sensitivity in hypertension. Renal and cardiovascular implications. Hypertension. 1994;23(4):531–50.PubMed CrossRef
176.Chrysant GS, Bakir S, Oparil S. Dietary salt reduction in hypertension—what is the evidence and why is it still controversial? Prog Cardiovasc Dis. 1999;42(1):23–38.PubMed CrossRef
177.Meng L, Fu B, Zhang T, Han Z, Yang M. Salt sensitivity of blood pressure in non-dialysis patients with chronic kidney disease. Ren Fail. 2014;36(3):345–50.PubMed CrossRef
178.Li N, Chen L, Yi F, Xia M, Li PL. Salt-sensitive hypertension induced by decoy of transcription factor hypoxia-inducible factor-1alpha in the renal medulla. Circ Res. 2008;102(9):1101–8.PubMed PubMedCentral CrossRef
179.Mattson DL, Higgins DJ. Influence of dietary sodium intake on renal medullary nitric oxide synthase. Hypertension. 1996;27(3 Pt 2):688–92.PubMed CrossRef
180.Zewde T, Mattson DL. Inhibition of cyclooxygenase-2 in the rat renal medulla leads to sodium-sensitive hypertension. Hypertension. 2004;44(4):424–8.PubMed CrossRef
181.Yang T, Singh I, Pham H, Sun D, Smart A, Schnermann JB, et al. Regulation of cyclooxygenase expression in the kidney by dietary salt intake. Am J Physiol. 1998;274(3 Pt 2):F481–9.PubMed
182.Harris RC, Breyer MD. Physiological regulation of cyclooxygenase-2 in the kidney. Am J Physiol Renal Physiol. 2001;281(1):F1–11.PubMed
183.Tan DY, Meng S, Cason GW, Manning Jr RD. Mechanisms of salt-sensitive hypertension: role of inducible nitric oxide synthase. Am J Physiol Regul Integr Comp Physiol. 2000;279(6):R2297–303.PubMed
184.Szentiványi Jr M, Zou AP, Mattson DL, Soares P, Moreno C, Roman RJ, et al. Renal medullary nitric oxide deficit of Dahl S rats enhances hypertensive actions of angiotensin II. Am J Physiol Regul Integr Comp Physiol. 2002;283(1):R266–72.PubMed CrossRef
185.Wang Z, Zhu Q, Xia M, Li PL, Hinton SJ, Li N. Hypoxia-inducible factor prolyl-hydroxylase 2 senses high-salt intake to increase hypoxia inducible factor 1alpha levels in the renal medulla. Hypertension. 2010;55(5):1129–36.PubMed PubMedCentral CrossRef
186.Li N, Yi F, Sundy CM, Chen L, Hilliker ML, Donley DK, et al. Expression and actions of HIF prolyl-4-hydroxylase in the rat kidneys. Am J Physiol Renal Physiol. 2007;292(1):F207–16.PubMed CrossRef
187.Zhu Q, Wang Z, Xia M, Li PL, Zhang F, Li N. Overexpression of HIF-1α transgene in the renal medulla attenuated salt sensitive hypertension in Dahl S rats. Biochim Biophys Acta. 2012;1822(6):936–41.PubMed PubMedCentral CrossRef
188.Zhu Q, Hu J, Han WQ, Zhang F, Li PL, Wang Z, et al. Silencing of HIF prolyl-hydroxylase 2 gene in the renal medulla attenuates salt-sensitive hypertension in Dahl S rats. Am J Hypertens. 2014;27(1):107–13.PubMed PubMedCentral CrossRef
189.Guo G, Winmill R, Arend M, Flippin L, Lin A, Klaus S, Liu D, Langsetmo I. Correction of anemia without exacerbation of hypertension in a rat model of chronic kidney disease: comparison of FG-2216 to recombinant erythropoietin [abstract]. J Am Soc Nephrol. 2008;19:654A.
190.Besarab A, Provenzano R, Fishbane S, Sun CH, Belo DS, Neff TB, Lee TT, Franco M, Leong R, Yu KHP. FG-4592 Oral hypoxia-inducible factor prolyl hydroxylase inhibitor corrects anemia in nondialysis CKD patients without IV Iron [abstract]. J Am Soc Nephrol. 2011;22:196A.
191.Locatelli F, Olivares J, Walker R, Wilkie M, Jenkins B, Dewey C, et al. Novel erythropoiesis stimulating protein for treatment of anemia in chronic renal insufficiency. Kidney Int. 2001;60(2):741–7.PubMed CrossRef
192.Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361(21):2019–32.PubMed CrossRef
193.Besarab A, Leong R, Franco M, Roberts BK, Lee T, Neff TB, Yu KHP. FG-4592, a novel oral hypoxia inducible factor (HIF) stabilizer, raises hemoglobin (Hb) in diabetic subjects with anemia of chronic kidney disease (CKD) [abstract]. 73rd Scientific Sessions of the American Diabetes Association; 2013 Jun 21-25; Chicago, IL, USA.
194.United States Securities and Exchange Commission, Washington, D.C. 20549. Form S-1 registration statement under the Securities Act of 1933. Akebia Therapeutics, Inc. [http://​www.​sec.​gov/​Archives/​edgar/​data/​1517022/​0001193125140551​04/​d629509ds1.​htm ]. Accessed 2015 Dec 21.
  • 作者单位:Farhanah Yousaf (1)
    Bruce Spinowitz (1)

    1. Division of Nephrology, NewYork-Presbyterian/Queens, 56-45 Main Street, Flushing, New York, NY, 11355, USA
  • 刊物主题:Internal Medicine; Cardiology; Metabolic Diseases; Nephrology; Primary Care Medicine; General Practice / Family Medicine;
  • 出版者:Springer US
  • ISSN:1534-3111
  • 文摘
    Anemia of chronic kidney disease (CKD) is common and is associated with diminished quality of life, cognitive impairment, cardiovascular morbidity, hospitalizations, and mortality. As the prevalence of end-stage renal disease continues to rise, the management of anemia represents a growing economic burden. Erythropoiesis-stimulating agents (ESA) are the mainstay of anemia management but their use is limited due to the associated cardiovascular adverse events. Prolyl hydroxylase domain enzyme (PHD) inhibitors are a new class of drugs that stabilize the hypoxia-inducible factors and are under clinical investigation for the treatment of renal anemia. The advantages of PHD inhibitors include the oral route of administration, improved iron profile, restoration of diurnal rhythm of erythropoietin secretion, and endogenous erythropoietin production near physiological range. Emerging but limited data indicates a small blood pressure lowering effect of PHD inhibitors. The effect of PHD inhibitors on cardiovascular endpoints and the potential risks of CKD progression and pulmonary hypertension remains to be addressed in the ongoing clinical trials.

    © 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号

    地址:北京市海淀区学院路29号 邮编:100083

    电话:办公室:(+86 10)66554848;文献借阅、咨询服务、科技查新:66554700