Hepatic HIF-2 regulates erythropoietic responses to hypoxia in renal anemia

Pinelopi P. Kapitsinou, Qingdu Liu, Travis L. Unger, Jennifer Rha, Olena Davidoff, Brian Keith, Jonathan A. Epstein, Sheri L. Moores, Connie L. Erickson-Miller, Volker H. Haase

Research output: Contribution to journalArticlepeer-review

201 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3039-3048
Number of pages10
JournalBlood
Volume116
Issue number16
DOIs
StatePublished - Oct 21 2010

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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