Deletion of Iron Regulatory Protein 1 Causes Polycythemia and Pulmonary Hypertension in Mice through Translational Derepression of HIF2α
Open accessAbstract
Iron regulatory proteins (Irps) 1 and 2 posttranscriptionally control the expression of transcripts that contain iron-responsive element (IRE) sequences, including ferritin, ferroportin, transferrin receptor, and hypoxia-inducible factor 2α (HIF2α). We report here that mice with targeted deletion of Irp1 developed pulmonary hypertension and polycythemia that was exacerbated by a low-iron diet. Hematocrits increased to 65% in iron-starved mice, and many polycythemic mice died of abdominal hemorrhages. Irp1 deletion enhanced HIF2α protein expression in kidneys of Irp1(-/-) mice, which led to increased erythropoietin (EPO) expression, polycythemia, and concomitant tissue iron deficiency. Increased HIF2α expression in pulmonary endothelial cells induced high expression of endothelin-1, likely contributing to the pulmonary hypertension of Irp1(-/-) mice. Our results reveal why anemia is an early physiological consequence of iron deficiency, highlight the physiological significance of Irp1 in regulating erythropoiesis and iron distribution, and provide important insights into the molecular pathogenesis of pulmonary hypertension.
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When the mechanism fails, as in Irp1-knockout mice, a transient polycythemia occurs in the relatively iron-deficient young animals, which reverts in adult mice with iron sufficiency.
“When the mechanism fails, as in Irp1-knockout mice, a transient polycythemia occurs in the relatively iron-deficient young animals, which reverts in adult mice with iron sufficiency.64,65”
From Iron metabolism and iron disorders revisited in the hepcidin era (2020) · cites this paper as [64]
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Cites
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- Authors
- Ghosh, M. C., Zhang, D.-L., Jeong, S. Y., Kovtunovych, G., Ollivierre-Wilson, H., Noguchi, A., Tu, T., Senecal, T., Robinson, G., Crooks, D. R., Tong, W.-H., Ramaswamy, K., Singh, A., Graham, B. B., Tuder, R. M., Yu, Z.-X., Eckhaus, M., Lee, J., Springer, D. A., & Rouault, T. A.
- Affiliations
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (US)
- National Institutes of Health (US)
- University of Colorado Anschutz (US)
- University of Nebraska–Lincoln (US)
- Corresponding author
- Rouault, Tracey A.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2013-02
- Volume
- 17
- Issue
- 2
- Pages
- 271-281
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC3569856
- OpenAlex
- W1991852898
- Cited by
- 183
- References
- 9
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 9 · 2023: 11 · 2022: 9 · 2021: 18 · 2020: 18 · 2019: 15 · 2018: 18 · 2017: 15 · 2016: 8 · 2015: 23 · 2014: 14 · 2013: 8
- FWCI
- 12.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute
- Eunice Kennedy Shriver National Institute of Child Health and Human Development
- National Institutes of Health (RC1HL100849)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
- Keywords
- iron regulatory protein 1, polycythemia, pulmonary hypertension, HIF-2α, iron deficiency, erythropoiesis, erythropoietin, endothelin-1, iron-responsive element, post-transcriptional regulation, anemia, low-iron diet
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Animals, Diet, Erythropoietin, Hematopoiesis, Extramedullary, Gastrointestinal Hemorrhage, Hypertension, Pulmonary, Iron, Longevity, Models, Biological, Nerve Degeneration, Organ Specificity, Polycythemia, Protein Biosynthesis, Transcriptional Activation, Gene Deletion, Endothelin-1, Iron Regulatory Protein 1, Iron Regulatory Protein 2, Endothelial Cells, Mice, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins
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