Erythropoietin (Epo) and its Receptors in Rat Models of Type I and II Diabetic Retinopathy

Abstract

Purpose: : Diabetes Mellitus induces vascular and neural sequelae. We hypothesize that diabetic retinopathy (DR) is both a vasculopathy and neuroretinopathy and that molecules such as erythropoietin influence both compartments. Originally described as a haematopoietic hormone, Epo is now known to be neuroprotective and pro–angiogenic; it is upregulated by hypoxia. Epo is neuroprotective in at least five experimental models of retinal degeneration and in a model of diabetic peripheral neuropathy. Case reports of patients receiving Epo for diabetic renal anemia suggest visual improvement. By contrast, new studies correlating Epo expression with proliferative DR in human vitreous samples, and animal studies of non–diabetic proliferative retinopathy, suggest that Epo could worsen retinal neovascularization. The purpose of this study was to investigate the distribution of Epo and its receptor (EpoR) in the retina of diabetic animals and to observe their correlation with markers of the neuronal and vascular compartments. We also wished to correlate Epo/EpoR expression with markers of reactive gliopathy and Epo–regulated components of the cell death pathway.

Methods: : We investigated the streptozotacin (STZ; 65mg/ip) induced model of Type I diabetes, and the genetically obese Zucker diabetic fatty (ZDF) (leptin receptor –/–) rat. Controls included non–STZ and Zucker lean (lepR+/–). Epo, EpoR, GFAP, vimentin, and CD105 were analyzed by epifluorescent immunohistochemistry and confirmed by PCR.

Results: : Epo and EpoR were observed at low levels in the normal, non–diabetic retinas, as expected. Expression was significantly increased in the retinas of both diabetic models, most notably in the inner retina in association with changes in GFAP that included ectopic staining in vimentin and Muller cells. Staining of both Epo and EpoR was clearly outside of the vascular tree in the neuroglial parenchyma.

Conclusions: : The presence of Epo and its receptors in early pre–proliferative diabetic retina is consistent with the notion that Epo could function as an endogenous neuroprotective molecule. While not addressed in this short–term study, it is possible that ongoing and inappropriate Epo expression could accelerate retinal vasculopathy. We will further characterize the time–course of Epo and EpoR in DR and ask whether increased early neuroglial expression gives way to vascular expression later in disease.

Keywords: diabetic retinopathy • neuroprotection