Hypoxia-inducible factor–2 (HIF-2) regulates hepatic erythropoietin in vivo
Erinn B. Rankin, Mangatt P. Biju, Qingdu Liu, Travis L. Unger, Jennifer Rha, Randall S. Johnson, M. Celeste Simon, Brian Keith, Volker H. Haase
Erinn B. Rankin, Mangatt P. Biju, Qingdu Liu, Travis L. Unger, Jennifer Rha, Randall S. Johnson, M. Celeste Simon, Brian Keith, Volker H. Haase
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Research Article

Hypoxia-inducible factor–2 (HIF-2) regulates hepatic erythropoietin in vivo

Abstract

Erythropoiesis is critically dependent on erythropoietin (EPO), a glycoprotein hormone that is regulated by hypoxia-inducible factor (HIF). Hepatocytes are the primary source of extrarenal EPO in the adult and express HIF-1 and HIF-2, whose roles in the hypoxic induction of EPO remain controversial. In order to define the role of HIF-1 and HIF-2 in the regulation of hepatic EPO expression, we have generated mice with conditional inactivation of Hif-1α and/or Hif-2α (Epas1) in hepatocytes. We have previously shown that inactivation of the von Hippel–Lindau tumor suppressor pVHL, which targets both HIFs for proteasomal degradation, results in increased hepatic Epo production and polycythemia independent of Hif-1α. Here we show that conditional inactivation of Hif-2α in pVHL-deficient mice suppressed hepatic Epo and the development of polycythemia. Furthermore, we found that physiological Epo expression in infant livers required Hif-2α but not Hif-1α and that the hypoxic induction of liver Epo in anemic adults was Hif-2α dependent. Since other Hif target genes such phosphoglycerate kinase 1 (Pgk) were Hif-1α dependent, we provide genetic evidence that HIF-1 and HIF-2 have distinct roles in the regulation of hypoxia-inducible genes and that EPO is preferentially regulated by HIF-2 in the liver.

Authors

Erinn B. Rankin, Mangatt P. Biju, Qingdu Liu, Travis L. Unger, Jennifer Rha, Randall S. Johnson, M. Celeste Simon, Brian Keith, Volker H. Haase

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Figure 4

Hepatic Epo expression in anemic mice is Hif-2α dependent.

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Hepatic Epo expression in anemic mice is Hif-2α dependent. ...
(A and B) Hif-1α and Hif-2α proteins are stabilized in the livers of anemic mice as determined by Western blot analysis. Nuclear protein extracts were isolated from livers of albumin-Cre mutant mice of the indicated genotypes. Nuclear protein extracts isolated from the thymus (Thy) of Vhlh-deficient mice was used as a positive Hif-1α protein control. Ponceau S staining is shown to demonstrate equal protein loading. (C–F) Real-time PCR analysis of hepatic Epo, Pgk,Bnip3, and Trf expression in anemic albumin-Cre mutant mice. White bars represent mice with hematocrit values of approximately 45%; gray bars, approximately 27%; and black bars, approximately 15%. Bars represent average mRNA transcript levels of 3 mice for each group; error bars indicate SEM. *P < 0.05, **P < 0.001 compared with control mice (Cre–) with the same range of hematocrit as determined by Student’s t test.