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-1alpha and/or Hif-2alpha (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-1alpha. Here we show that conditional inactivation of Hif-2alpha in pVHL-deficient mice suppressed hepatic Epo and the development of polycythemia. Furthermore, we found that physiological Epo expression in infant livers required Hif-2alpha but not Hif-1alpha and that the hypoxic induction of liver Epo in anemic adults was Hif-2alpha dependent. Since other Hif target genes such phosphoglycerate kinase 1 (Pgk) were Hif-1alpha 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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 117 Issue 4 Pg. 1068-77 (Apr 2007) ISSN: 0021-9738 [Print] United States
• PMID: 17404621 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• Erythropoietin
• endothelial PAS domain-containing protein 1
• Von Hippel-Lindau Tumor Suppressor Protein
• VHL protein, mouse

Topics

• Animals
• Basic Helix-Loop-Helix Transcription Factors (physiology)
• Disease Models, Animal
• Erythropoietin (genetics)
• Gene Expression Regulation
• Hepatocytes (physiology)
• Liver (physiology)
• Mice
• Mice, Knockout
• Polycythemia Vera (genetics)
• Von Hippel-Lindau Tumor Suppressor Protein (genetics)
• von Hippel-Lindau Disease (genetics)