Hypoxia Pathway Proteins are Master Regulators of Erythropoiesis
Abstract
:1. Introduction
2. HIF Transcription Factors and Their Modulators
3. Erythropoiesis: A Multistep Process
4. EPO/EPOR Axis: Hypoxia Pathway in Action
5. Hypoxia-Mediated EPO Production at Other Sites
6. EPOR and HIF Axis
7. Iron Metabolism: HPP as Cucial Contributors
8. Anemia and CKD—The PHD–HIF Axis and Therapeutic Targeting
9. HIF–EPO–FGF-23 Axis: PHD2/HIF Inhibition
10. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Stage of Erythropoiesis/Iron Metabolism | Factors | Key Role in Erythropoiesis | Regulation by HIF/EPO | References |
---|---|---|---|---|
Early stages of development of erythroid progenitors | GATA-1 | Initiates erythropoiesis Regulates the transcription of several erythroid differentiation-related genes | HRE present in GATA-1 and GATA-1 regulation by HIF1. EPO protects GATA-1 from caspase-induced degradation | [62,63,64,65] |
Pro-erythroblasts to late erythroblasts | EPO | Key cytokine essential for growth, survival, and differentiation of RBC’s | HIF2 directly regulates EPO | [52,66,67,68] |
EPOR | Essential for erythropoiesis and action of EPO | Some evidence on regulation by hypoxia and HIFs | [69,70,71] | |
Late stage maturation/Apoptosis | FAS, FAS-L | Apoptosis and arrest maturation | Downregulation by EPO | [72] |
Iron metabolism | Hepcidin | A crucial regulator of iron metabolism; suppresses ferroportin | Direct and indirect suppression by hypoxia, HIF, and EPO | [73,74,75,76,77] |
Ferroportin (FPN) | A critical factor that facilitates iron export from the cells | Regulated by HIF2a and hepcidin | [78] | |
Erythroferrone (ERFE) | Suppresses hepcidin production | Upregulation by EPO | [79,80] | |
Transferrin (TF) | Required for transporting iron | Regulation by HIF1 | [61] | |
Transferrin receptor (TFR1) | Plays role in erythroid differentiation/ role in iron uptake | Induced by HIF1 and hypoxia | [59,60] | |
FGF-23 | Potential role in erythropoiesis. blockage of FGF-23 results in increased erythropoiesis | Increased by EPO | [66,81,82,83] |
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Watts, D.; Gaete, D.; Rodriguez, D.; Hoogewijs, D.; Rauner, M.; Sormendi, S.; Wielockx, B. Hypoxia Pathway Proteins are Master Regulators of Erythropoiesis. Int. J. Mol. Sci. 2020, 21, 8131. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218131
Watts D, Gaete D, Rodriguez D, Hoogewijs D, Rauner M, Sormendi S, Wielockx B. Hypoxia Pathway Proteins are Master Regulators of Erythropoiesis. International Journal of Molecular Sciences. 2020; 21(21):8131. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218131
Chicago/Turabian StyleWatts, Deepika, Diana Gaete, Diego Rodriguez, David Hoogewijs, Martina Rauner, Sundary Sormendi, and Ben Wielockx. 2020. "Hypoxia Pathway Proteins are Master Regulators of Erythropoiesis" International Journal of Molecular Sciences 21, no. 21: 8131. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218131