Herpesvirus entry mediator regulates hypoxia-inducible factor–1α and erythropoiesis in mice
Yukimi Sakoda, … , Lieping Chen, Koji Tamada
Yukimi Sakoda, … , Lieping Chen, Koji Tamada
Published November 14, 2011
Citation Information: J Clin Invest. 2011;121(12):4810-4819. https://doi.org/10.1172/JCI57332.
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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 4

HVEM stimulation promotes erythropoiesis via renal Epo production.

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HVEM stimulation promotes erythropoiesis via renal Epo production. (A) W...
(A) WT mice were injected i.p. with 150 μg control Ig or HM3.30. Serum Epo levels were measured at the indicated time points. (B) WT mice were first injected i.p. with 150 μg control Ig or anti-Epo neutralizing mAb before receiving treatment as in A 4 hours later. After 4 days, absolute number of Ter119+CD45– cells per spleen was measured by flow cytometry. (C) WT mice were treated as in A. After 8 and 16 hours, RNA was isolated from the kidney and liver, and analyzed by real-time PCR for the expression of Epo. PCR products were normalized to the expression of 18S and shown as fold change compared to the control. (D) WT mice received bilateral nephrectomy or sham operation and, 1 hour after surgery, were treated as in A (except that injections were i.v.). After 16 hours, serum Epo level was measured. (E and F) WT and Hvem–/– mice were injected i.v. with 3 mg/kg cisplatin daily from day 0 to day 3. (E) On days 2 and 4, serum Epo level was measured. (F) On day 8, peripheral blood Hb level was measured. Data represent mean ± SEM (n ≥ 4 mice per group). **P < 0.01; *P < 0.05.