title: Hepatic HIF-2 regulates erythropoietic responses to hypoxia in renal anemia.
abstract: The kidney is the main physiologic source of erythropoietin (EPO) in the adult and responds to decreases in tissue oxygenation with increased EPO production. Although studies in mice with liver-specific or global gene inactivation have shown that hypoxia-inducible factor 2 (Hif-2) plays a major role in the regulation of Epo during infancy and in the adult, respectively, the contribution of renal HIF-2 signaling to systemic EPO homeostasis and the role of extrarenal HIF-2 in erythropoiesis, in the absence of kidney EPO, have not been examined directly. Here, we used Cre-loxP recombination to ablate Hif-2α in the kidney, whereas Hif-2-mediated hypoxia responses in the liver and other Epo-producing tissues remained intact. We found that the hypoxic induction of renal Epo is completely Hif-2 dependent and that, in the absence of renal Hif-2, hepatic Hif-2 takes over as the main regulator of serum Epo levels. Furthermore, we provide evidence that hepatocyte-derived Hif-2 is involved in the regulation of iron metabolism genes, supporting a role for HIF-2 in the coordination of EPO synthesis with iron homeostasis.
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-2372, USA.
authors.forename: Pinelopi P
authors.initials: PP
authors.lastname: Kapitsinou
authors.forename: Qingdu
authors.initials: Q
authors.lastname: Liu
authors.forename: Travis L
authors.initials: TL
authors.lastname: Unger
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rha
authors.forename: Olena
authors.initials: O
authors.lastname: Davidoff
authors.forename: Brian
authors.initials: B
authors.lastname: Keith
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Epstein
authors.forename: Sheri L
authors.initials: SL
authors.lastname: Moores
authors.forename: Connie L
authors.initials: CL
authors.lastname: Erickson-Miller
authors.forename: Volker H
authors.initials: VH
authors.lastname: Haase
mesh_terms: D000740:Anemia / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D004920:Erythropoiesis; D004921:Erythropoietin / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism*; D007501:Iron / Q000378:metabolism; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004921:Erythropoietin; D007501:Iron; D014157:Transcription Factors; D000099162:Endothelial PAS Domain-Containing Protein 1; C485502:HIF-2 protein, mouse