- Open Access
Erythropoietin Receptor (EpoR) Agonism Is Used to Treat a Wide Range of Disease
Molecular Medicine volume 19, pages62–64(2013)
The erythropoietin receptor (EpoR) was discovered and described in red blood cells (RBCs), stimulating its proliferation and survival. The target in humans for EpoR agonists drugs appears clear—to treat anemia. However, there is evidence of the pleitropic actions of erythropoietin (Epo). For that reason, rhEpo therapy was suggested as a reliable approach for treating a broad range of pathologies, including heart and cardiovascular diseases, neurodegenerative disorders (Parkinson’s and Alzheimer’s disease), spinal cord injury, stroke, diabetic retinopathy and rare diseases (Friedreich ataxia). Unfortunately, the side effects of rhEpo are also evident. A new generation of nonhematopoietic EpoR agonists drugs (asialoEpo, Cepo and ARA 290) have been investigated and further developed. These EpoR agonists, without the erythropoietic activity of Epo, while preserving its tissue-protective properties, will provide better outcomes in ongoing clinical trials. Nonhematopoietic EpoR agonists represent safer and more effective surrogates for the treatment of several diseases such as brain and peripheral nerve injury, diabetic complications, renal ischemia, rare diseases, myocardial infarction, chronic heart disease and others.
In principle, the erythropoietin receptor (EpoR) was discovered and described in red blood cell (RBC) progenitors, stimulating its proliferation and survival. Erythropoietin (Epo) is mainly synthesized in fetal liver and adult kidneys (1–3). Therefore, it was hypothesized that Epo act exclusively on erythroid progenitor cells. Accordingly, the target in humans for EpoR agonists drugs (such as recombinant erythropoietin [rhEpo], in general, called erythropoiesis-simulating agents) appears clear (that is, to treat anemia). However, evidence of a kaleidoscope of pleitropic actions of Epo has been provided (4,5). The Epo/EpoR axis research involved an initial journey from laboratory basic research to clinical therapeutics. However, as a consequence of clinical observations, basic research on Epo/EpoR comes back to expand its clinical therapeutic applicability.
Although kidney and liver have long been considered the major sources of synthesis, Epo mRNA expression has also been detected in the brain (neurons and glial cells), lung, heart, bone marrow, spleen, hair follicles, reproductive tract and osteoblasts (6–17). Accordingly, EpoR was detected in other cells, such as neurons, astrocytes, microglia, immune cells, cancer cell lines, endothelial cells, bone marrow stromal cells and cells of heart, reproductive system, gastrointestinal tract, kidney, pancreas and skeletal muscle (18–27). Conversely, Sinclair et al. (28) reported data questioning the presence or function of EpoR on non-hematopoietic cells (endothelial, neuronal and cardiac cells), suggesting that further studies are needed to confirm the diversity of EpoR. Elliott et al. (29) also showed that EpoR is virtually undetectable in human renal cells and other tissues with no detectable EpoR on cell surfaces. These results have raised doubts about the preclinical basis for studies exploring pleiotropic actions of rhEpo (30).
For the above-mentioned data, a return to basic research studies has become necessary, and many studies in animal models have been initiated or have already been performed. The effect of rhEpo administration on angiogenesis, myogenesis, shift in muscle fiber types and oxidative enzyme activities in skeletal muscle (4,31), cardiac muscle mitochondrial biogenesis (32), cognitive effects (31), antiapoptotic and antiinflammatory actions (33–37) and plasma glucose concentrations (38) has been extensively studied. Neuro- and cardioprotection properties have been mainly described. Accordingly, rhEpo therapy was suggested as a reliable approach for treating a broad range of pathologies, including heart and cardiovascular diseases, neurodegenerative disorders (Parkinson’s and Alzheimer’s disease), spinal cord injury, stroke, diabetic retinopathy and rare diseases (Friedreich ataxia).
Unfortunately, the side effects of rhEpo are also evident. Epo is involved in regulating tumor angiogenesis (39) and probably in the survival and growth of tumor cells (25,40,41). rhEpo administration also induces serious side effects such as hypertension, polycythemia, myocardial infarction, stroke and seizures, platelet activation and increased thromboembolic risk, and immunogenicity (42–46), with the most common being hypertension (47,48). A new generation of non-hematopoietic EpoR agonists drugs have hence been investigated and further developed in animals models. These compounds, namely asialoerythropoietin (asialoEpo) and carbamylated Epo (Cepo), were developed for preserving tissue-protective properties but reducing the erythropoietic activity of native Epo (49,50). These drugs will provide better outcome in ongoing clinical trials. The advantage of using nonhematopoietic Epo analogs is to avoid the stimulation of hematopoiesis and thereby the prevention of an increased hematocrit with a subsequent procoagulant status or increased blood pressure. In this regard, a new study by van Rijt et al. has shed new light on this topic (51). A new non-hematopoietic EpoR agonist analog named ARA 290 has been developed, promising cytoprotective capacities to prevent renal ischemia/reperfusion injury (51). ARA 290 is a short peptide that has shown no safety concerns in preclinical and human studies. In addition, ARA 290 has proven efficacious in cardiac disorders (52,53), neuropathic pain (54) and sarcoidosis-induced chronic neuropathic pain (55). Thus, ARA 290 is a novel non-hematopoietic EpoR agonist with promising therapeutic options in treating a wide range of pathologies and without increased risks of cardiovascular events.
Overall, this new generation of EpoR agonists without the erythropoietic activity of Epo while preserving tissue-protective properties of Epo will provide better outcomes in ongoing clinical trials (49,50). Nonhematopoietic EpoR agonists represent safer and more effective surrogates for the treatment of several diseases, such as brain and peripheral nerve injury, diabetic complications, renal ischemia, rare diseases, myocardial infarction, chronic heart disease and others.
The authors declare that they have no competing interests as defined by Molecular Medicine, or other interests that might be perceived to influence the results and discussion reported in this paper.
Digicaylioglu M, et al. (1995) Localization of specific erythropoietin binding sites in defined areas of the mouse brain. Proc. Natl. Acad. Sci. U. S. A. 92: 3717–20.
Jelkmann W. (1992) Erythropoietin: structure, control of production, and function. Physiol. Rev. 72: 449–89.
Haase VH. (2013) Regulation of erythropoiesis by hypoxia-inducible factors. Blood Rev. 27:41–53.
Rotter R, et al. (2008) Erythropoietin improves functional and histological recovery of traumatized skeletal muscle tissue. J. Orthop. Res. 26:1618–26.
Jelkmann W. (2007) Erythropoietin after a century of research: younger than ever. Eur. J. Haematol. 78:183–205.
Dame C, et al. (1998) Erythropoietin mRNA expression in human fetal and neonatal tissue. Blood. 92:3218–25.
Marti HH, et al. (1996) Erythropoietin gene expression in human, monkey and murine brain. Eur. J. Neurosci. 8:666–76.
Marti HH, et al. (1997) Detection of erythropoietin in human liquor: intrinsic erythropoietin production in the brain. Kidney Int. 51:416–8.
Bernaudin M, et al. (2000) Neurons and astrocytes express EPO mRNA: oxygen-sensing mechanisms that involve the redox-state of the brain. Glia. 30:271–8.
Magnanti M, et al. (2001) Erythropoietin expression in primary rat Sertoli and peritubular myoid cells. Blood. 98:2872–4.
Dame C, et al. (2000) Erythropoietin gene expression in different areas of the developing human central nervous system. Brain Res. Dev. Brain Res. 125:69–74.
Fandrey J, Bunn HF. (1993) In vivo and in vitro regulation of erythropoietin mRNA: measurement by competitive polymerase chain reaction. Blood. 81:617–23.
Bodo E, et al. (2007) Human hair follicles are an extrarenal source and a nonhematopoietic target of erythropoietin. FASEB J. 21:3346–54.
Yasuda Y, et al. (1998) Estrogen-dependent production of erythropoietin in uterus and its implication in uterine angiogenesis. J. Biol. Chem. 273:25381–7.
Kobayashi T, et al. (2002) Epididymis is a novel site of erythropoietin production in mouse reproductive organs. Biochem. Biophys. Res. Commun. 296:145–51.
Masuda S, et al. (2000) The oviduct produces erythropoietin in an estrogen- and oxygen-dependent manner. Am. J. Physiol. Endocrinol. Metab. 278:E1038–44.
Rankin EB, et al. (2012) The HIF signaling pathway in osteoblasts directly modulates erythropoiesis through the production of EPO. Cell. 149:63–74.
Acs G, et al. (2001) Erythropoietin and erythropoietin receptor expression in human cancer. Cancer Res. 61:3561–5.
Lundby C, et al. (2008) Erythropoietin receptor in human skeletal muscle and the effects of acute and long-term injections with recombinant human erythropoietin on the skeletal muscle. J. Appl. Physiol. 104:1154–60.
Broxmeyer HE. (2011) Erythropoietin surprises: an immune saga. Immunity. 34:6–7.
Nairz M, et al. (2011) Erythropoietin contrastingly affects bacterial infection and experimental colitis by inhibiting nuclear factor-kappaB-inducible immune pathways. Immunity. 34:61–74.
Nairz M, et al. (2012) The pleiotropic effects of erythropoietin in infection and inflammation. Microbes Infect. 14:238–46.
Brines M, Cerami A. (2006) Discovering erythropoietin’s extra-hematopoietic functions: biology and clinical promise. Kidney Int. 70:246–50.
Choi D, et al. (2010) Erythropoietin protects against diabetes through direct effects on pancreatic beta cells. J. Exp. Med. 207:2831–42.
Hand CC, Brines M. (2011) Promises and pitfalls in erythopoietin-mediated tissue protection: are nonerythropoietic derivatives a way forward? J. Investig. Med. 59:1073–82.
McGee SJ, et al. (2012) Effects of erythropoietin on the bone microenvironment. Growth Factors. 30:22–8.
Sytkowski AJ. (2011) The neurobiology of erythropoietin. Cell. Mol. Neurobiol. 31:931–7.
Sinclair AM, et al. (2010) Functional erythropoietin receptor is undetectable in endothelial, cardiac, neuronal, and renal cells. Blood. 115:4264–72.
Elliott S, et al. (2011) Lack of expression and function of erythropoietin receptors in the kidney. Nephrol. Dial. Transplant. 27:2733–45.
Jelkmann W, Elliott S. (2012) Erythropoietin and the vascular wall: the controversy continues. Nutr. Metab. Cardiovasc. Dis. 2012, Jun 6. [Epub ahead of print].
Lundby C, Olsen NV. (2011) Effects of recombinant human erythropoietin in normal humans. J. Physiol. 589:1265–71.
Carraway MS, et al. (2010) Erythropoietin activates mitochondrial biogenesis and couples red cell mass to mitochondrial mass in the heart. Circ. Res. 106:1722–30.
Prunier F, et al. (2012) Single high-dose erythropoietin administration immediately after reperfusion in patients with ST-segment elevation myocardial infarction: results of the erythropoietin in myocardial infarction trial. Am. Heart J. 163:200–7. e1.
Moon C, et al. (2003) Erythropoietin reduces myocardial infarction and left ventricular functional decline after coronary artery ligation in rats. Proc. Natl. Acad. Sci. U. S. A. 100:11612–7.
Parsa CJ, et al. (2003) A novel protective effect of erythropoietin in the infarcted heart. J. Clin. Invest. 112:999–1007.
Tamareille S, et al. (2009) Myocardial reperfusion injury management: erythropoietin compared with postconditioning. Am. J. Physiol. Heart Circ. Physiol. 297:H2035–43.
Prunier F, et al. (2007) Delayed erythropoietin therapy reduces post-MI cardiac remodeling only at a dose that mobilizes endothelial progenitor cells. Am. J. Physiol. Heart Circ. Physiol. 292:H522–9.
Cayla J, et al. (1999) Effects of recombinant erythropoietin (r-HuEPO) on plasma glucose concentration in endurance-trained rats. Acta Physiol. Scand. 166:247–9.
Ribatti D. (2010) Erythropoietin and tumor angiogenesis. Stem Cells Dev. 19:1–4.
Szenajch J, et al. (2010) The role of erythropoietin and its receptor in growth, survival and therapeutic response of human tumor cells: from clinic to bench—a critical review. Biochim. Biophys. Acta. 1806:82–95.
Oster HS, et al. (2012) Erythropoietin: the swinging pendulum. Leuk. Res. 36:939–44.
Shin SK, et al. (2012) Immunogenicity of recombinant human erythropoietin in Korea: a two-year cross-sectional study. Biologicals. 40:254–61.
Macdougall IC, et al. (2012) Antibody-mediated pure red cell aplasia in chronic kidney disease patients receiving erythropoiesis-stimulating agents: new insights. Kidney Int. 81:727–32.
Ponikowski P, et al. (2007) Effect of darbepoetin alfa on exercise tolerance in anemic patients with symptomatic chronic heart failure: a randomized, double-blind, placebo-controlled trial. J. Am. Coll. Cardiol. 49:753–62.
van Veldhuisen DJ, et al. (2007) Randomized, double-blind, placebo-controlled study to evaluate the effect of two dosing regimens of darbepoetin alfa in patients with heart failure and anaemia. Eur. Heart J. 28:2208–16.
Marchioli R, et al. (2013) Cardiovascular events and intensity of treatment in polycythemia vera. N. Engl. J. Med. 368:22–33.
Lubas A, et al. (2010) Renal vascular response to angiotensin II inhibition in intensive antihypertensive treatment of essential hypertension. Arch. Med. Sci. 6:533–8.
Banach M, et al. (2010) Controversies in hypertension treatment. Curr. Vasc. Pharmacol. 8:731–2.
Cicero AF, Ertek S. (2010) Preclinical and clinical evidence of nephro- and cardiovascular protective effects of glycosaminoglycans. Arch. Med. Sci. 6:469–77.
Durmaz O, et al. (2011) Recombinant human erythropoietin beta: the effect of weekly dosing on anemia, quality of life, and long-term outcomes in pediatric cancer patients. Pediatr. Hematol. Oncol. 28:461–8.
van Rijt WG, et al. (2013) ARA290, a non-erythropoietic EPO derivative, attenuates renal ischemia/reperfusion injury. J. Transl. Med. 11:9.
Joshi D, et al. (2012) Potential of novel EPO derivatives in limb ischemia. Cardiol. Res. Pract. 2012:213785.
Ahmet I, et al. (2011) A small nonerythropoietic helix B surface peptide based upon erythropoietin structure is cardioprotective against ischemic myocardial damage. Mol. Med. 17:194–200.
Swartjes M, et al. (2011) ARA290, a peptide derived from the tertiary structure of erythropoietin, produces long-term relief of neuropathic pain: an experimental study in rats and beta-common receptor knockout mice. Anesthesiology. 115:1084–92.
Heij L, et al. (2013) Safety and efficacy of ARA 290 in sarcoidosis patients with symptoms of small fiber neuropathy: a randomized, doubleblind pilot study. Mol. Med. 18:1430–6.
About this article
Cite this article
Sanchis-Gomar, F., Perez-Quilis, C. & Lippi, G. Erythropoietin Receptor (EpoR) Agonism Is Used to Treat a Wide Range of Disease. Mol Med 19, 62–64 (2013). https://doi.org/10.2119/molmed.2013.00025