Hyperhomocysteinemia disrupts retinal pigment epithelial structure and function with features of age-related macular degeneration

Abstract

// Ahmed S. Ibrahim 1,2,3 , Suchreet Mander 1,2 , Khaled A. Hussein 1,2,4 , Nehal M. Elsherbiny 1,3 , Sylvia B. Smith 2,5,6 , Mohamed Al-Shabrawey 1,2,5,6 and Amany Tawfik 1,2,5 1 Department of Oral Biology and Anatomy, College of Dental Medicine, Augusta University, Augusta, GA, USA 2 James and Jean Culver Vision Discovery Institute, Medical College of Georgia (MCG), Augusta University, Augusta, GA, USA 3 Department of Biochemistry and Clinical Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt 4 Oral and Dental Research Division, Department of Surgery and Medicine, National Research Center, Cairo, Egypt 5 Department of Cellular Biology and Anatomy, MCG, Augusta University, Augusta, GA, USA 6 Department of Ophthalmology, MCG, Augusta University, Augusta, GA, USA Correspondence to: Amany Tawfik, email: // Keywords : age related macular degeneration, hyperhomocysteinemia, retinal pigment epithelium, cystathionine-β-synthase and mouse, Gerotarget Received : December 23, 2015 Accepted : January 30, 2016 Published : February 14, 2016 Abstract The disruption of retinal pigment epithelial (RPE) function and the degeneration of photoreceptors are cardinal features of age related macular degeneration (AMD); however there are still gaps in our understanding of underlying biological processes. Excess homocysteine (Hcy) has been reported to be elevated in plasma of patients with AMD. This study aimed to evaluate the direct effect of hyperhomocysteinemia (HHcy) on structure and function of RPE. Initial studies in a mouse model of HHcy, in which cystathionine-β-synthase ( cbs ) was deficient, revealed abnormal RPE cell morphology with features similar to that of AMD upon optical coherence tomography (OCT), fluorescein angiography (FA), histological, and electron microscopic examinations. These features include atrophy, vacuolization, hypopigmentation, thickened basal laminar membrane, hyporeflective lucency, choroidal neovascularization (CNV), and disturbed RPE–photoreceptor relationship. Furthermore, intravitreal injection of Hcy per se in normal wild type (WT) mice resulted in diffuse hyper-fluorescence, albumin leakage, and CNV in the area of RPE. In vitro experiments on ARPE-19 showed that Hcy dose-dependently reduced tight junction protein expression, increased FITC dextran leakage, decreased transcellular electrical resistance, and impaired phagocytic activity. Collectively, our results demonstrated unreported effects of excess Hcy levels on RPE structure and function that lead to the development of AMD-like features.