Hepatic HIF-2 regulates erythropoietic responses to hypoxia in renal anemia.
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.
Kapitsinou
Pinelopi P
PP
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-2372, USA.
Liu
Qingdu
Q
Unger
Travis L
TL
Rha
Jennifer
J
Davidoff
Olena
O
Keith
Brian
B
Epstein
Jonathan A
JA
Moores
Sheri L
SL
Erickson-Miller
Connie L
CL
Haase
Volker H
VH
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
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