Elevated Erythropoietin mRNA and Protein Concentrations in the Developing Human Eye

Abstract

Erythropoietin (Epo) is an erythropoietic, neurotropic, and angiogenic factor, and may be involved in retinal development. Studies in adult diabetic retinopathy patients reveal significantly elevated vitreal Epo concentrations. It is unknown whether Epo plays a similar role in retinopathy of prematurity. We sought to determine whether Epo is present in the normally developing human eye. Fetal serum and vitreous samples were obtained from 12 to 24 wk gestation. RNA was extracted from isolated retina for Epo mRNA and hypoxia inducible factor-1␣ (HIF) mRNA determination by real-time polymerase chain reaction. Fetal serum was isolated from the umbilical cord. Serum and vitreous samples were analyzed for Epo protein by enzyme-linked immunosorbent serologic assay. In fetal retina, Epo mRNA increased with increasing gestational age, while HIF mRNA remained constant. Epo protein increased with increasing gestation in both vitreous and serum. At each gestational group measured (12-14, 15-17, 18 -20, and 21-24 wk), Epo concentrations were significantly greater in vitreous than in serum (p Ͻ 0.05). Epo mRNA and protein concentrations increase with increasing gestational age and are greater in the vitreous than serum. We speculate that changes in Epo production following preterm delivery might affect retinal vascular development.

Revisiting the role of erythropoietin for treatment of ocular disorders

“…In recent years, a study reported that there is a direct correlation of fetal retina EPO mRNA amount in vitreous humor with increasing gestational age. 13 This is further supported by Wu et al 14 on the involvement of EPO in the development of human eye. During the process of organogenesis in the eye, they discovered the expression of EPO, along with signal transducer activator-of-transcription (STAT)-5, EPOR, and pro-apoptotic protein Bcl-2-associated X (Bax) expressions throughout the lens and retinal development.…”

“…Following to the previous outcomes, 13,14 several studies further identified EPO in neural retina differentiation. Alternatively, EPO could facilitate the differentiation through binding with a heterodimer complex, consisting of EPOR and interleukin beta-common receptor (βcR; CD131).…”

“…14 Both studies concluded that the involvement of EPO during the eye development could be contributing to its protective role in preventing cell apoptosis (Figure 2). 13,14 Figure 2 outlines on the schematic model of cell signaling of EPO in guarding the eye development. It begins with binding of EPO to the homodimeric EPOR, present on the ocular progenitor cells.…”

“…2,13,14,98,99 Based on the positive pre-clinical outcomes with various animal models, 5,8,12,15 EPO may offer a promising future therapy for treatment of many common ocular disorders plaguing us today such as DR, retinal detachment, glaucoma, retinopathy of prematurity, AMD, and optic neuritis. Current clinical trials are using established recombinant EPO such as epoietin alfa 100,101 and darbepoietin, 100,102 which do not specifically target to correct nerve circuitry activity in the eye.…”

Safety and efficacy of intravitreal injection of recombinant erythropoietin for protection of photoreceptor cells in a rat model of retinal detachment

“…1 An increasing number of studies have demonstrated the neuroprotective effects of EPO and its receptor, by anti-apoptotic mechanisms. Several studies have indicated that EPO can protect photoreceptor cells from the effects of lightinduced and hereditary retinal dystrophy; [2][3][4][5] protect retinal neurons from ischemiareperfusion injury, 6 and retinal ganglion cells after acute and chronic ocular hypertension; [7][8][9] promote ganglion cell survival and axonal regeneration after optic nerve transection; [10][11][12] attenuate inflammation in multiple sclerosis optic neuritis; 13,14 reduce the permeability of the retinal barrier and protect retinal neurons in diabetic retinopathy; [15][16][17][18] relieve diabetic macular edema; 19 enhance the stability of hypoxic retinal vessels; 20,21 and has a neuroprotective role in pigment epithelial cells subjected to photo-oxidative damage. 22 EPO exerts its biological effects through interaction with EPO receptor (EPOR).…”