Oxygen-dependent and tissue-specific regulation of erythropoietin gene expression
Abstract
Hypoxia-inducible expression of the gene encoding for the glycoprotein hormone erythropoietin (EPO) is the paradigm of oxygen-regulated gene expression. EPO is the main regulator of red blood cell production and more than 100 years of research on the regulation of EPO production have led to the identification of a widespread cellular oxygen sensing mechanism. Central to this signaling cascade is the transcription factor complex hypoxia-inducible factor-1 (HIF-1). Meanwhile, it is known that HIF-1 controls more than 50 oxygen-dependent genes and is now recognized as the main regulator of oxygen homoeostasis in the body. In addition to hypoxic induction, expression of the EPO gene is tightly regulated in a tissue-specific manner. During ontogeny, production of EPO required for erythropoiesis is switched from the fetal liver to the kidneys. Here EPO is mainly synthesized in adulthood. Production of EPO has also been found in organs where it has nonerythropoietic functions: EPO is important for development of the brain and is neuroprotective, whereas it stimulates angiogenesis in the reproductive tract and possibly in other organs. Understanding oxygen and tissue-specific regulation of EPO production is of high relevance for physiology. Moreover, this knowledge might be useful for new therapies to treat human diseases.
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Redox-modulated HIF regulation operates in intact organisms, not only in cell culture.
“Importantly, redox-modulated HIF regulation operates in intact organisms, not only in cell culture.”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [210]
Redox-sensitive regulation of erythropoietin production and HIF activity occurs in physiological settings.
“Studies by Fandrey and colleagues demonstrated redox-sensitive regulation of erythropoietin production and HIF activity in physiological settings [210]”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [210]
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HIF inhibition: Current strategies and clinical challenges
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“Studies by Fandrey and colleagues demonstrated redox-sensitive regulation of erythropoietin production and HIF activity in physiological settings [210], while developmental analyses by Adelman, Maltepe, Simon, and co-workers established that HIF signaling is indispensable for embryonic oxygen…”
- Authors
- Fandrey, J.
- Affiliations
- University of Duisburg-Essen (DE)
- Corresponding author
- Fandrey, Joachim
- ORCID
- Fandrey, Joachim
- Venue
- American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
- Publisher
- American Physiological Society
- Published
- 2004-06
- Volume
- 286
- Issue
- 6
- Pages
- R977-R988
- ISSN
- 0363-6119 (ISSN-L)
- 1522-1490
- OpenAlex
- W2005538515
- Cited by
- 243
- References
- 20
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 7 · 2023: 2 · 2022: 7 · 2021: 6 · 2020: 8 · 2019: 9 · 2018: 7 · 2017: 14 · 2016: 7 · 2015: 8 · 2014: 12 · 2013: 12 · 2012: 12
- FWCI
- 2.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Regulatory, Integrative and Comparative Physiology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Keywords
- erythropoietin, HIF-1, oxygen sensing, oxygen homeostasis, tissue-specific gene expression, erythropoiesis, fetal liver, kidney, neuroprotection, angiogenesis
- MeSH terms
- Animals, DNA-Binding Proteins, Erythropoietin, Gene Expression Regulation, Humans, Molecular Conformation, Nuclear Proteins, Organ Specificity, Oxygen, Regulatory Sequences, Nucleic Acid, RNA, Messenger, Transcription Factors, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit
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