EPO is a glycoprotein of mass 30.4 kDa, consisting of 165 amino-acid core and oligosaccharide side chains that comprise ∼40% of the mass. The polypeptide moiety is sufficient for binding to EPO receptor (EPOR), while carbohydrate moiety is required for secretion and protection against metabolism.
EPO and EPOR are expressed in wide range of tissues. Kidneys are the main site of EPO production, as kidneys function as oxygen and haematocrit sensor. Peritubular fibroblasts of the renal cortex produce EPO in response to hypoxia; hypoxia-inducible factor HIF-2α regulates EPO gene expression, and EPO stimulates the production of red blood cells (erythropoiesis) in the bone marrow. EPO production is decreased in chronic kidney disease, leading to anaemia and hypoxia. Normally, the tips of the juxtamedullary region of the cortical labyrinth are the place where the oxygen balance is most sensitive to changes in haematocrit, and where the EPO is produced. Anaemia causes the partial pressure of oxygen to drop in more superficial regions of the renal cortex, leading to EPO production in increasingly larger volumes of the cortex (Dunn et al., 2007). Hypoxia stimulates EPO production also in other organs, including liver and brain. Lung and heart diseases that cause chronic hypoxia can lead to high serum EPO levels.
Recombinant human erythropoietin (rhuEpo) is used to treat anaemia.
EPOR is a type I transmembrane protein that belongs to the cytokine receptor superfamily. The amount of EPOR in the endoplasmic reticulum is much higher than what is located on cell surfaces. Intracellular signalling cascade is started when EPO binds to two EPORs on the cell membrane, forming EPOR homodimer. EPO and EPOR monomer can also combine with βcR (CD131), which is a shared receptor subunit of many receptors, including IL-3, IL-5, and GM-CSF receptors; this may be responsible for the cytoprotective effects of EPO (Peng et al., 2020). TfR2 can associate with EPO receptor, affecting erythropoiesis in bone marrow (Richard & Verdier, 2020).
In the bone marrow, EPOR is expressed in erythroid progenitors (mainly colony-forming unit erythroid, CFU-E, cells), megakaryocytes, myeloid cells, and endothelial progenitors. EPOR is also expressed in the heart, lungs, immune system, brain, gastrointestinal tract, endocrine systems, reproductive tissues, and in some types of cancer. In most organs, EPO and EPOR form a local paracrine feedback system, with EPOR and EPO expressing cells in close proximity. In vascular system, EPO and EPOR are expressed in endothelial cells and smooth muscle cells. EPOR is also expressed on cardiac myocytes. In the CNS, EPOR are expressed on neurons, and EPO is produced by astrocytes. In peripheral nervous system, EPOR is expressed in Schwann cells. Hypoxia increases the expression of EPO and EPOR in CNS.
Soluble form of EPO receptor (sEPOR) results from alternative splicing of the EPOE mRNA. It binds and sequestrates EPO, decreasing its availability (Khankin et al., 2010).
Recombinant human erythropoietin (rhuEpo), that is used to treat anaemia, can be labelled with positron-emitting isotopes. [68Ga]DOTA-rhuEpo has shown favourable kinetic properties and specific EPOR binding in mice studies, and could be used to assess EPOR status of tumours (Fuge et al., 2015).
Cornelio-Martínez S, Castañeda-Arellano R. Erythropoietin regulates signaling pathways associated with neuroprotective events. Exp Brain Res. 2022; 240(5): 1303-1315. doi: 10.1007/s00221-022-06331-9.
Haim Ohana Y, Liron T, Prutchi-Sagiv S, Mittelman M, Souroujon MC, Neumann D. Erythropoietin. In: Handbook of Biologically Active Peptides. Elsevier, 2013. doi: 10.1016/B978-0-12-385095-9.00221-9.
Tomc J, Debeljak N. Molecular insights into the oxygen-sensing pathway and erythropoietin expression regulation in erythropoiesis. Int J Mol Sci. 2021; 22(13): 7074. doi: 10.3390/ijms22137074.
Updated at: 2023-02-01
Created at: 2023-01-15
Written by: Vesa Oikonen