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 6

Hif-2 regulates hepatic Epo expression in infant mice.

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Hif-2 regulates hepatic Epo expression in infant mice. (...
(A) Relative Epo mRNA levels in the livers and kidneys (K) of P2, P10, P20, and P60 mice. Bars represent the average Epo mRNA transcript level of 3 mice for each condition. (B) Genomic PCR analysis of DNA isolated from the tail and liver of albumin–Hif-2α mutant mice at P2 and P10. Note that the ratio of the recombined (1-lox) allele to the unrecombined (2-lox) Hif-2α allele increased between P2 and P10. (C) Relative Epo mRNA expression levels in P10 albumin–Hif-2α (Hif-2α–/–) and albumin–Hif-1α (Hif-1α–/–) and Cre-recombinase–negative control littermates (WT). Bars represent the mean Epo mRNA transcript level for WT albumin–Hif-2α littermates (n = 12) and albumin–Hif-2α mutants (n = 13) (left) and albumin–Hif-1α mutants and littermate controls (n = 10 each) (left). (D) Hemoglobin concentrations and red blood cell numbers in blood collected from 10-day-old albumin-Cre mutant and control mice. Bars represent the mean values for albumin–Hif-2α controls and mutants (n = 12 each), albumin–Hif-1α controls (n = 18), and albumin–Hif-1α mutants (n = 11). Error bars represent SEM. *P < 0.05 compared with littermate controls as determined by Student’s t test.