Herpesvirus entry mediator regulates hypoxiainducible factor-1α and erythropoiesis in mice

Yukimi Sakoda, Sudarshan Anand, Yuming Zhao, Jang June Park, Yingjia Liu, Atsuo Kuramasu, Nico Van Rooijen, Ling Chen, Scott E. Strome, Wayne W. Hancock, Lieping Chen, Koji Tamada

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Erythropoiesis, the production of red blood cells, must be tightly controlled to ensure adequate oxygen delivery to tissues without causing thrombosis or stroke. Control of physiologic and pathologic erythropoiesis is dependent predominantly on erythropoietin (EPO), the expression of which is regulated by hypoxia-inducible factor (HIF) activity in response to low oxygen tension. Accumulating evidence indicates that oxygen-independent mediators, including inflammatory stimuli, cytokines, and growth factors, also upregulate HIF activity, but it is unclear whether these signals also result in EPO production and erythropoiesis in vivo. Here, we found that signaling through herpesvirus entry mediator (HVEM), a molecule of the TNF receptor superfamily, promoted HIF-1α activity in the kidney and subsequently facilitated renal Epo production and erythropoiesis in vivo under normoxic conditions. This Epo upregulation was mediated by increased production of NO by renal macrophages. Hvem-deficient mice displayed impaired Epo expression and aggravated anemia in response to erythropoietic stress. These data reveal that HVEM signaling functions to promote HIF-1α; activity and Epo production, and thus to regulate erythropoiesis. Furthermore, our findings suggest that this molecular mechanism could represent a therapeutic target for Epo-responsive diseases, including anemia.

Original languageEnglish (US)
Pages (from-to)4810-4819
Number of pages10
JournalJournal of Clinical Investigation
Volume121
Issue number12
DOIs
StatePublished - Dec 1 2011
Externally publishedYes

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Receptors, Tumor Necrosis Factor, Member 14
Erythropoiesis
Hypoxia-Inducible Factor 1
Oxygen
Erythropoietin
Kidney
Anemia
Up-Regulation
Tumor Necrosis Factor Receptors
Intercellular Signaling Peptides and Proteins
Thrombosis
Erythrocytes
Stroke
Macrophages
Cytokines

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Herpesvirus entry mediator regulates hypoxiainducible factor-1α and erythropoiesis in mice. / Sakoda, Yukimi; Anand, Sudarshan; Zhao, Yuming; Park, Jang June; Liu, Yingjia; Kuramasu, Atsuo; Van Rooijen, Nico; Chen, Ling; Strome, Scott E.; Hancock, Wayne W.; Chen, Lieping; Tamada, Koji.

In: Journal of Clinical Investigation, Vol. 121, No. 12, 01.12.2011, p. 4810-4819.

Research output: Contribution to journalArticle

Sakoda, Y, Anand, S, Zhao, Y, Park, JJ, Liu, Y, Kuramasu, A, Van Rooijen, N, Chen, L, Strome, SE, Hancock, WW, Chen, L & Tamada, K 2011, 'Herpesvirus entry mediator regulates hypoxiainducible factor-1α and erythropoiesis in mice', Journal of Clinical Investigation, vol. 121, no. 12, pp. 4810-4819. https://doi.org/10.1172/JCI57332
Sakoda, Yukimi ; Anand, Sudarshan ; Zhao, Yuming ; Park, Jang June ; Liu, Yingjia ; Kuramasu, Atsuo ; Van Rooijen, Nico ; Chen, Ling ; Strome, Scott E. ; Hancock, Wayne W. ; Chen, Lieping ; Tamada, Koji. / Herpesvirus entry mediator regulates hypoxiainducible factor-1α and erythropoiesis in mice. In: Journal of Clinical Investigation. 2011 ; Vol. 121, No. 12. pp. 4810-4819.
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