Soluble Erythropoietin Receptor is Present in the Mouse Brain and is Required for the Ventilatory Acclimatization to Hypoxia

Overview

Journal J Physiol

Specialty Physiology

Date 2007 Jun 23

PMID 17584830

Citations 24

Authors

Jorge Soliz

Max Gassmann

Vincent Joseph

Affiliations

Soon will be listed here.

Abstract

While erythropoietin (Epo) and its receptor (EpoR) have been widely investigated in brain, the expression and function of the soluble Epo receptor (sEpoR) remain unknown. Here we demonstrate that sEpoR, a negative regulator of Epo's binding to the EpoR, is present in the mouse brain and is down-regulated by 62% after exposure to normobaric chronic hypoxia (10% O2 for 3 days). Furthermore, while normoxic minute ventilation increased by 58% in control mice following hypoxic acclimatization, sEpoR infusion in brain during the hypoxic challenge efficiently reduced brain Epo concentration and abolished the ventilatory acclimatization to hypoxia (VAH). These observations imply that hypoxic downregulation of sEpoR is required for adequate ventilatory acclimatization to hypoxia, thereby underlying the function of Epo as a key factor regulating oxygen delivery not only by its classical activity on red blood cell production, but also by regulating ventilation.

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References

Prabhakar N, Jacono F . Cellular and molecular mechanisms associated with carotid body adaptations to chronic hypoxia. High Alt Med Biol. 2005; 6(2):112-20. DOI: 10.1089/ham.2005.6.112. View

Jelkmann W . Effects of erythropoietin on brain function. Curr Pharm Biotechnol. 2005; 6(1):65-79. DOI: 10.2174/1389201053167257. View

Eckardt K, Kurtz A . Regulation of erythropoietin production. Eur J Clin Invest. 2005; 35 Suppl 3:13-9. DOI: 10.1111/j.1365-2362.2005.01525.x. View

Hundahl C, Stoltenberg M, Fago A, Weber R, Dewilde S, Fordel E . Effects of short-term hypoxia on neuroglobin levels and localization in mouse brain tissues. Neuropathol Appl Neurobiol. 2005; 31(6):610-7. DOI: 10.1111/j.1365-2990.2005.00657.x. View

Stockmann C, Fandrey J . Hypoxia-induced erythropoietin production: a paradigm for oxygen-regulated gene expression. Clin Exp Pharmacol Physiol. 2006; 33(10):968-79. DOI: 10.1111/j.1440-1681.2006.04474.x. View

Soliz J, Joseph V, Soulage C, Becskei C, Vogel J, Pequignot J . Erythropoietin regulates hypoxic ventilation in mice by interacting with brainstem and carotid bodies. J Physiol. 2005; 568(Pt 2):559-71. PMC: 1474739. DOI: 10.1113/jphysiol.2005.093328. View

Kilic U, Kilic E, Soliz J, Bassetti C, Gassmann M, Hermann D . Erythropoietin protects from axotomy-induced degeneration of retinal ganglion cells by activating ERK-1/-2. FASEB J. 2004; 19(2):249-51. DOI: 10.1096/fj.04-2493fje. View

Kline D, Yang T, Premkumar D, Thomas A, Prabhakar N . Blunted respiratory responses to hypoxia in mutant mice deficient in nitric oxide synthase-3. J Appl Physiol (1985). 2000; 88(4):1496-508. DOI: 10.1152/jappl.2000.88.4.1496. View

Joseph V, Soliz J, PEQUIGNOT J, Sempore B, Cottet-Emard J, Dalmaz Y . Gender differentiation of the chemoreflex during growth at high altitude: functional and neurochemical studies. Am J Physiol Regul Integr Comp Physiol. 2000; 278(4):R806-16. DOI: 10.1152/ajpregu.2000.278.4.R806. View

10.

Powell F, Huey K, Dwinell M . Central nervous system mechanisms of ventilatory acclimatization to hypoxia. Respir Physiol. 2000; 121(2-3):223-36. DOI: 10.1016/s0034-5687(00)00130-4. View

11.

Powell F, Dwinell M, Aaron E . Measuring ventilatory acclimatization to hypoxia: comparative aspects. Respir Physiol. 2000; 122(2-3):271-84. DOI: 10.1016/s0034-5687(00)00165-1. View

12.

Chikuma M, Masuda S, Kobayashi T, Nagao M, Sasaki R . Tissue-specific regulation of erythropoietin production in the murine kidney, brain, and uterus. Am J Physiol Endocrinol Metab. 2000; 279(6):E1242-8. DOI: 10.1152/ajpendo.2000.279.6.E1242. View

13.

Lipton A, Johnson M, MacDonald T, Lieberman M, Gozal D, Gaston B . S-nitrosothiols signal the ventilatory response to hypoxia. Nature. 2001; 413(6852):171-4. DOI: 10.1038/35093117. View

14.

Stroka D, Burkhardt T, Desbaillets I, Wenger R, Neil D, Bauer C . HIF-1 is expressed in normoxic tissue and displays an organ-specific regulation under systemic hypoxia. FASEB J. 2001; 15(13):2445-53. DOI: 10.1096/fj.01-0125com. View

15.

Kline D, Peng Y, Manalo D, Semenza G, Prabhakar N . Defective carotid body function and impaired ventilatory responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1 alpha. Proc Natl Acad Sci U S A. 2002; 99(2):821-6. PMC: 117389. DOI: 10.1073/pnas.022634199. View

16.

Joseph V, Soliz J, Soria R, Pequignot J, Favier R, Spielvogel H . Dopaminergic metabolism in carotid bodies and high-altitude acclimatization in female rats. Am J Physiol Regul Integr Comp Physiol. 2002; 282(3):R765-73. DOI: 10.1152/ajpregu.00398.2001. View

17.

Westphal G, Braun K, Debus J . Detection and quantification of the soluble form of the human erythropoietin receptor (sEpoR) in the growth medium of tumor cell lines and in the plasma of blood samples. Clin Exp Med. 2002; 2(1):45-52. DOI: 10.1007/s102380200006. View

18.

Fisher J . Erythropoietin: physiology and pharmacology update. Exp Biol Med (Maywood). 2003; 228(1):1-14. DOI: 10.1177/153537020322800101. View

19.

Sasaki R . Pleiotropic functions of erythropoietin. Intern Med. 2003; 42(2):142-9. DOI: 10.2169/internalmedicine.42.142. View

20.

Gassmann M, Heinicke K, Soliz J, Ogunshola O . Non-erythroid functions of erythropoietin. Adv Exp Med Biol. 2004; 543:323-30. DOI: 10.1007/978-1-4419-8997-0_22. View