Hypoxia induced downregulation of hepcidin is mediated by platelet derived growth factor BB
Open accessAbstract
OBJECTIVE: Hypoxia affects body iron homeostasis; however, the underlying mechanisms are incompletely understood. DESIGN: Using a standardised hypoxia chamber, 23 healthy volunteers were subjected to hypoxic conditions, equivalent to an altitude of 5600 m, for 6 h. Subsequent experiments were performed in C57BL/6 mice, CREB-H knockout mice, primary hepatocytes and HepG2 cells. RESULTS: Exposure of subjects to hypoxia resulted in a significant decrease of serum levels of the master regulator of iron homeostasis hepcidin and elevated concentrations of platelet derived growth factor (PDGF)-BB. Using correlation analysis, we identified PDGF-BB to be associated with hypoxia mediated hepcidin repression in humans. We then exposed mice to hypoxia using a standardised chamber and observed downregulation of hepatic hepcidin mRNA expression that was paralleled by elevated serum PDGF-BB protein concentrations and higher serum iron levels as compared with mice housed under normoxic conditions. PDGF-BB treatment in vitro and in vivo resulted in suppression of both steady state and BMP6 inducible hepcidin expression. Mechanistically, PDGF-BB inhibits hepcidin transcription by downregulating the protein expression of the transcription factors CREB and CREB-H, and pharmacological blockade or genetic ablation of these pathways abrogated the effects of PDGF-BB toward hepcidin expression. CONCLUSIONS: Hypoxia decreases hepatic hepcidin expression by a novel regulatory pathway exerted via PDGF-BB, leading to increased availability of circulating iron that can be used for erythropoiesis.
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In hypoxia hepcidin is also suppressed in vitro by soluble hemojuvelin, released by furin, an effect unclear in vivo, and by platelet-derived growth factor-BB in volunteers exposed to hypoxia.
“In hypoxia hepcidin is also suppressed in vitro by soluble hemojuvelin, released by furin,53 an effect unclear in vivo, and by platelet-derived growth factor-BB in volunteers exposed to hypoxia.54”
From Iron metabolism and iron disorders revisited in the hepcidin era (2020) · cites this paper as [54]
Hypoxia-induced proteins HIF-1 or PDGF-BB reduce hepcidin expression, enhancing iron delivery for erythropoiesis.
“and several proteins induced by hypoxia such as hypoxia inducible factor-1 (HIF-1) or platelet derived growth factor BB (PDGF-BB) reduce hepcidin expression, thereby enhancing iron delivery for erythropoiesis (Peyssonnaux et al., 2007; Sonnweber et al., 2014).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Sonnweber et al., 2014
Hepcidin expression is repressed by hypoferremia, anemia, tissue hypoxia, and hormones such as GDF15, erythroferrone, PDGF-BB, and testosterone.
“and repressed in response to: (i) hypoferremia, that is, lower than normal levels of circulating Fe, (ii) anemia, (iii) tissue hypoxia, and (iv) hormones, for example, growth and differentiation factors 15, erythroferrone, platelet-derived growth factor-BB (PDGF-BB) and testosterone [62][63][64][65].”
From The Iron age of host–microbe interactions (2015) · cites this paper as [64]
PDGF-BB inhibits hepcidin transcription.
“such as PDGF-BB, also inhibit hepcidin transcription [64] (Fig 3).”
From The Iron age of host–microbe interactions (2015) · cites this paper as [64]
Hypoxia has a similar effect on hepcidin that is mediated via platelet-derived growth factor isoform BB, which may enable the required increase of hemoglobin levels at high altitude.
“Hypoxia has a similar effect on HAMP that is mediated via platelet-derived growth factor isoform BB (PDGF-BB), which may enable the required increase of Hb levels at high altitude [65].”
From Iron deficiency or anemia of inflammation?: Differential diagnosis and mechanisms of anemia of inflammation (2016) · cites this paper as [65]
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“In hypoxia hepcidin is also suppressed in vitro by soluble hemojuvelin, released by furin,(53) an effect unclear in vivo, and by platelet-derived growth factor-BB in volunteers exposed to hypoxia.(54) Proposed models of hepcidin regulation in different conditions are depicted in Figure 2A-D.”
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Self-citation
- Authors
- Sonnweber, T., Nachbaur, D., Schroll, A., Nairz, M., Seifert, M., Demetz, E., Haschka, D., Mitterstiller, A.-M., Kleinsasser, A., Burtscher, M., Trübsbach, S., Murphy, A. T., Wroblewski, V., Witcher, D. R., Mleczko-Sanecka, K., Vecchi, C., Muckenthaler, M. U., Pietrangelo, A., Theurl, I., & Weiss, G.
- Affiliations
- Innsbruck Medical University (AT)
- Universität Innsbruck (AT)
- Department of Anaesthesia and Intensive Care Medicine, Medical University Innsbruck, Innsbruck, Austria
- Eli Lilly (United States) (US)
- Department of Pediatric Oncology, Haematology and Immunology, University Hospital of Heidelberg, Heidelberg, Germany
- Azienda Ospedaliero-Universitaria di Modena (IT)
- University Hospital Heidelberg (DE)
- Corresponding author
- Theurl, Igor
- ORCID
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2014-03-05
- Volume
- 63
- Issue
- 12
- Pages
- 1951-1959
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- OpenAlex
- W2139604659
- Cited by
- 145
- References
- 50
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 6 · 2023: 14 · 2022: 10 · 2021: 8 · 2020: 11 · 2019: 14 · 2018: 19 · 2017: 12 · 2016: 15 · 2015: 21 · 2014: 8
- FWCI
- 13.23
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- cc-by
- Locations
- Gut (publishedVersion)
- PubMed (publishedVersion)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- HighWire Press Open Archive (submittedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Keywords
- hypoxia, hepcidin, PDGF-BB, iron homeostasis, CREB, BMP6, serum iron, erythropoiesis, high altitude, hepatocytes
- MeSH terms
- Becaplermin, Adult, Animals, Hypoxia, Disease Models, Animal, Erythropoiesis, Female, Hematologic Agents, Humans, Iron, Male, Mice, Inbred C57BL, Platelet-Derived Growth Factor, Down-Regulation, Proto-Oncogene Proteins c-sis, Mice, Hep G2 Cells, Healthy Volunteers, Hepcidins
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