Herpesvirus entry mediator regulates hypoxia-inducible 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
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
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Research Article Hematology

Herpesvirus entry mediator regulates hypoxia-inducible factor–1α and erythropoiesis in mice

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.

Authors

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

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Figure 7

NO is essential for HM3.30-mediated Epo production.

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NO is essential for HM3.30-mediated Epo production. (A and B) WT C57BL/6...
(A and B) WT C57BL/6 mice were injected i.p. with 150 μg control Ig or HM3.30 on day 0. Mice were subsequently treated i.p. with or without 100 mg/kg l-NAME every 24 hours for 4 days (n = 3 per group). (A) Percent reticulocytes was assessed by flow cytometry on day 4. (B) RNA was extracted from the kidneys on day 1, and Epo mRNA expression level was determined by real-time PCR. (C) WT or iNOS–/– mice were injected i.p. with 150 μg control Ig or HM3.30. After 4 hours, RNA was isolated from the kidneys, and Epo mRNA expression was assessed by real-time PCR. Mean ± SEM are shown. *P < 0.01; **P < 0.001.