Alterations of retinal pigment epithelium cause AMD-like retinopathy in senescence-accelerated OXYS rats

Anton M. Markovets,Natalia G. Kolosova,Anzhella Zh. Fursova,Valeriya B. Saprunova,Lora E. Bakeeva,Anna A. Zhdankina

doi:10.18632/aging.100243

Abstract

Pathogenesis of age-related macular degeneration (AMD), the leading cause of blindness in the world, remains poorly understood. This makes it necessary to create animal models for studying AMD pathogenesis and to design new therapeutic approaches. Here we showed that retinopathy in OXYS rats is similar to human AMD according to clinical signs, morphology, and vascular endothelium growth factor (VEGF) and pigment epithelium-derived factor (PEDF) genes expression. Clinical signs of retinopathy OXYS rats manifest by the age 3 months against the background of significantly reduced expression level of VEGF and PEDF genes due to the decline of the amount of retinal pigment epithelium (RPE) cells and alteration of choroidal microcirculation. The disruption in OXYS rats' retina starts at the age of 20 days and appears as reduce the area of RPE cells but does not affect their ultrastructure. Ultrastructural pathological alterations of RPE as well as develop forms of retinopathy are observed in OXYS rats from age 12 months and manifested as excessive accumulation of lipofuscin in RPE regions adjacent to the rod cells, whirling extentions of the basement membrane into the cytoplasm. These data suggest that primary cellular degenerative alterations in the RPE cells secondarily lead to choriocapillaris atrophy and results in complete loss of photoreceptor cells in the OXYS rats' retina by the age of 24 months.

Highlights

Age-related macular degeneration (AMD), the leading cause of blindness in the world, is under intensive investigation but its pathogenesis remains poorly understood
Our morphological investigation confirmed that the same retinal structure is involved in pathological processes in OXYS rats as in humans AMD [25,26]
Primary cellular degenerative alterations have been observed first in the retinal pigment epithelium (RPE) cells of OXYS rats, which secondarily lead to damage in the choriocapillaries and photoreceptor cells

Summary

Introduction

Age-related macular degeneration (AMD), the leading cause of blindness in the world, is under intensive investigation but its pathogenesis remains poorly understood. According to the clinical signs, it is usually defined two forms of this disease: atrophic (80-90%) and exudative (about 10% of cases). Atrophic (or dry) form is characterized by progressive degeneration of retinal pigment epithelium (RPE) and photoreceptor cells. Exudative (or wet) form is characterized by edema, spot bleeding, inflammation and choroidal neovascularization (CNV) which is a cause of ~90% of blindness from AMD. Degeneration of RPE can create prerequisites for disease development and cause an alteration of choroid vessels [3,4]. RPE cells secrete many regulatory factors, including VEGF and PEDF [1,5,6,7,8]. It is well established that vascular endothelial growth factor A (VEGF-A), the member of a large family of growth factors, is a key regulator of physiological and pathological angiogenesis and vascular permeability [9,10]

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