Physiology and pharmacology of erythropoietin

Abstract

Human erythropoietin (Epo) is a 30.4 kDa glycoprotein hormone composed of a single 165 amino acid residues chain to which four glycans are attached. The kidneys are the primary sources of Epo, its synthesis is controlled by hypoxia-inducible transcription factors (HIFs). Epo is an essential factor for the viability and proliferation of erythrocytic progenitors. Whether Epo exerts cytoprotection outside the bone marrow still needs to be clarified. Epo deficiency is the primary cause of the anemia in chronic kidney disease (CKD). Treatment with recombinant human Epo (rhEpo, epoetin) can be beneficial not only in CKD but also for other indications, primarily anemia in cancer patients receiving chemotherapy. Considering unwanted events, the administration of rhEpo or its analogs may increase the incidence of thromboembolism. The expiry of the patents for the original epoetins has initiated the production of similar biological medicinal products ('biosimilars'). Furthermore, analogs (darbepoetin alfa, methoxy PEG-epoetin beta) with prolonged survival in circulation have been developed ('biobetter'). New erythropoiesis-stimulating agents are in clinical trials. These include compounds that augment erythropoiesis directly (e.g. Epo mimetic peptides or activin A binding protein) and chemicals that act indirectly by stimulating endogenous Epo synthesis (HIF stabilizers).

Keywords: Anemia; Chronic kidney disease; Erythrocytic progenitors; Hypoxia; Recombinant human erythropoietin; Red blood cells.

Fig. 1

Scheme of erythropoiesis. The kidneys are the main site of the production of erythropoietin (Epo). The EPO enhancer is activated by the hypoxia-inducible transcription factor complex HIF-1β/HIF-2α. Supported by co-factors such as p300 the HIF complex binds to the hypoxia-response element (HRE) activating EPO expression. In bone marrow, Epo promotes the survival, proliferation and differentiation of erythrocytic progenitors, particularly the colony-forming units-erythroid (CFU-Es). Starting about four days after an increase in Epo levels, more reticulocytes enter the blood stream.

Fig. 2

Scheme of Epo receptor signaling. Endogenous Epo, its recombinant analogs and Epo-mimetic peptides can bind to the homodimeric EpoR. The EpoR then recruits JAK-2 that catalyzes EpoR/JAK-2 transphosphorylation. The phosphorylated EpoR induces activation of the signal transducer and activator of transcription 5 (STAT-5), the phosphatidyl-inositol 3-kinase (PI-3K)/AKT, and the SH2 adaptor protein C (SHC)/mitogen-activated protein kinase (MAPK) pathways. STAT-5 induces the expression of anti-apoptotic proteins (for example Bcl-x_L). PI-3K and MAPK prevent pro-apoptotic proteins (Bax, Bad) from activating caspases, specific cysteine proteases otherwise executing apoptosis. In addition, MAPK activates genes promoting cell proliferation.