Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo.
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.
Rankin
Erinn B
EB
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6144, USA.
Biju
Mangatt P
MP
Liu
Qingdu
Q
Unger
Travis L
TL
Rha
Jennifer
J
Johnson
Randall S
RS
Simon
M Celeste
MC
Keith
Brian
B
Haase
Volker H
VH
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000235:genetics*; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000502:physiology*; D008099:Liver / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D011087:Polycythemia Vera / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*; D006623:von Hippel-Lindau Disease / Q000235:genetics*; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D004921:Erythropoietin; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C494469:VHL protein, mouse