Hepatic HIF-2 regulates erythropoietic responses to hypoxia in renal anemia
Open accessAbstract
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.
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Hepatic HIF can be sufficiently stimulated pharmacologically to correct anemia resulting from inadequate EPO production or inflammatory conditions.
“hepatic HIF can be sufficiently stimulated by pharmacologic means to correct anemia that results from inadequate EPO production or from inflammatory conditions. 24, 34”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [24]
In adults, the liver retains the ability to produce EPO in response to moderate/severe hypoxia or pharmacologic HIF activation.
“However, in adults, the liver retains its ability to produce EPO in response to moderate/severe hypoxia or to pharmacologic HIF activation. 23–25”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [24]
Inactivation of HIF-2α in the kidney completely ablated the renal EPO response to normobaric hypoxia, phlebotomy-induced anemic hypoxia, or a HIF-activating compound.
“Inactivation of HIF-2α in the kidney completely ablated the renal EPO response in mice subjected to normobaric hypoxia (10% O2 for 10 days), phlebotomy-induced anemic hypoxia, or treatment with a HIF activating compound. 109”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [109]
In the context of anemic hypoxia, both HIF-1 and HIF-2 are activated.
“In the context of anemic hypoxia, both HIF-1 and HIF-2 are activated.”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [24]
Pharmacological inactivation of PHD enzymes with 2OG analogs has the potential to benefit patients with anemia that results from inadequate EPO production.
“and has the potential to benefit patients with anemia that results from inadequate EPO production.”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [24]
Pharmacological inactivation of PHD enzymes with 2OG analogs increases serum EPO levels in animal models and in humans.
“Pharmacological inactivation of PHD enzymes with 2OG analogs increases serum EPO levels in animal models and in humans”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [24]
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Self-citation
- Authors
- Kapitsinou, P. P., Liu, Q., Unger, T. L., Rha, J., Davidoff, O., Keith, B., Epstein, J. A., Moores, S. L., Erickson-Miller, C. L., & Haase, V. H.
- Affiliations
- Vanderbilt University (US)
- Department of Medicine,
- Abramson Cancer Center (US)
- University of Pennsylvania (US)
- GlaxoSmithKline (United States) (US)
- Oncology Translational Research, GlaxoSmithKline, Collegeville, PA
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2010-10-21
- Volume
- 116
- Issue
- 16
- Pages
- 3039-3048
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC2974609
- OpenAlex
- W2087098834
- Cited by
- 307
- References
- 48
- Citations by year
- 2026: 13 · 2025: 13 · 2024: 13 · 2023: 18 · 2022: 21 · 2021: 17 · 2020: 25 · 2019: 22 · 2018: 15 · 2017: 20 · 2016: 25 · 2015: 18 · 2014: 27 · 2013: 20 · 2012: 17
- FWCI
- 12.01
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Blood (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA100787)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK080821, R01DK081646)
- Topics
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Keywords
- HIF-2, erythropoietin, anemia of chronic kidney disease, hypoxia, erythropoiesis, iron metabolism, iron homeostasis, hypoxia-inducible factor
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Anemia, Animals, Hypoxia, Erythropoiesis, Erythropoietin, Iron, Kidney, Liver, Transcription Factors, Mice, Knockout, Mice, Basic Helix-Loop-Helix Proteins
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