Diabetes mellitus (DM) is a multi organic disease with a high incidence in the population, whose main cause is a carbohydrate metabolism disorder. One of the most common and at the same time, one of the most challenging chronic complications of DM is diabetic retinopathy (DR). Diabetic retinopathy leads to changes in the small blood vessels of the eye, and DR is nowadays considered as one of the leading causes of the impaired visual function and blindness, with significant socio-economic consequences on the working population which it affects (1).
Changed properties of blood vessels in DM and DR, lead to the increased liquid permeability which manifests as bleeding, oedema, and exudates in the eye. Another critical point in DM and DR pathogenesis is ischemia of the ocular tissues, which, through the production of vasoproliferative, angiogenic factors leads to neovascularisation - the growth of pathological blood vessels in the eye. These vessels have poor wall quality, and they will further lead to a vicious circle of new tissue ischemia and bleeding. The increased vascular permeability and pathologic neovascularisation are considered two major vascular pathogenic pathways for the development of diabetic retinopathy (2).
The development of DR has been studied for decades. It is well-known that local angiogenic factors in the eye play a dominant role, but recent studies, indicate the importance of systemic angiogenic growth factors, as well (3,4). One of angiogenic factors in our body is erythropoietin, and it is the body’s natural control mechanism for adjusting red blood cell count in response to the stressor. However, several important effects of EPO in the body are independent of its hematopoietic activity, and this is how EPO causes diabetic retinopathy changes (5,6).
A growth factor is a substance that stimulates cell growth, proliferation, and differentiation. Most frequently these factors work as cytokines and hormones. The most important representatives of growth factors are epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), insulin-like growth factor (IGF), erythropoietin (EPO), thrombopoietin (TPO), etc. (7)
Erythropoietin is a glycoprotein by its structure, which is composed of 166 amino acids. It is a pleiotropic cytokine, and a hormone with the function of circulatory growth factor (6, 8). It is produced mainly in the kidneys, with only in a small part in the liver (10%); the primary stimulus for its releasing is tissue hypoxia. It acts by binding to transmembrane erythropoietin receptors (EPOR), which are primarily found on hematopoietic cells, but can also be found on the endothelial, myocardial, neural cells, and as well on the cells of liver, uterus, and retina (9, 10). By binding to its receptor, erythropoietin activates physiological signalling cascade (including JAK 2 kinase signal-transducing, and STAT signalling cascade), as a response to hypoxia. There are recently discovered naturally occurring EPO mutations at specific activation sites of EPO, and this is how attenuation or modelling of EPO signalling in hematopoiesis leads to anaemia and other pathologic conditions (6). Circulating erythropoietin primarily affects hematopoietic cells, and by stimulating angiogenesis, it is even considered as tumour-cells stimulator (11,12).
There are theories about erythropoietic induction of neovascularisation caused by inflammation or ischemia. This induction occurs by mobilising the endothelial progenitor cells from the bone marrow, and thus increasing the number of cells in the circulation. From the existing capillaries and postcapillary venules, new blood vessels are being formed by degradation of the basal membrane of the blood vessel, migration of the endothelial cells and their mitosis, with the formation of bourgeons, lumens and vascular loops. All these steps represent angiogenesis that has to be distinguished from vasculogenesis (13). Vasculogenesis occurs by the differentiation of endothelial cells from angioblasts. Angiogenesis can be physiological and pathological. Physiological angiogenesis represents a balance between proangiogenic and antiangiogenic factors in an organism, and occurs in the reproductive cycle, pregnancy and wound healing (14, 15). Pathological angiogenesis occurs in neoplastic diseases leading to the acceleration of disease progression, and it is present in many other pathological conditions, like in diabetic retinopathy (16, 17, 18).
Numerous new studies indicate the main role of angiogenic growth factors on the development of proliferative diabetic retinopathy, and VEGF is considered to be the most important one (19), followed by erythropoietin, IGF-1, PDGF, etc. Intraocular synthesis of proangiogenic factors is in counterbalance with the production of antiangiogenic ones. It is considered that erythropoietin can have direct role in pathophysiology of diabetic retinopathy. However, there are still contradictory opinions about whether the role is aggravating or protective. It has been proved that erythropoietin significantly correlates with the origin of proliferative diabetic retinopathy (20). In DM, and conditions of hypoglycemia and hypoxia, the increased number of erythropoietin receptors appear on retinal cells. Some authors consider this might be how retinal tissues survive in unfavourable conditions like in DM, inducing the increased binding of erythropoietin molecules (21). In experimental rats with DM, intravitreal injection of EPO caused the increased number of erythropoietin receptors (EPOR) in neurosensory retina, with a protective effect against retinal neovascularisation and degenerative changes of photoreceptors (22, 23).
In certain researches it is found that the same EPO injection slows down retinal cells' death and promotes the function of hematoretinal barrier. Therefore EPO is being considered as one of the new therapeutical options in the treatment of early DR and diabetic macular oedema (9, 24). There is a recent discovery of naturally occurring nonhematopoietic variant of EPO hormone, which can activate only part of the signalling cascade, and therefore manifest only partial activation of EPO receptor, which could prove significant in the future regarding the application of new line drugs for new clinical conditions, apart from the already used ones.
However, there are different theories among the authors regarding the favourable influence of EPO on the progression of non-proliferative and proliferative DR. Some data show the improvement of DR by blocking of the production and effects of EPO in the eye (25).
Normal or low concentrations of erythropoietin are found in conditions of primary polycythemia, some erythropoietin-independent anaemias, but also in kidney-derived anaemia (26). The importance of reduced concentration of erythropoietin is clinically confirmed in early diabetic nephropathy, as it resulted in anaemia which worsened diabetic retinopathy (27). Also, in curing anaemia of renal origin, EPO given intravenously had positive effects on macular oedema, improved visual acuity in patients with DR and also led to the reduction of exudative maculopathy and proliferative changes of the disease (28, 29).