The Tight Junction Associated Signalling Proteins ZO-1 and ZONAB Regulate Retinal Pigment Epithelium Homeostasis in Mice

Cell-cell adhesion regulates the development and function of epithelia by providing mechanical support and by guiding cell proliferation and differentiation. The tight junction (TJ) protein zonula occludens (ZO)-1 regulates cell proliferation and gene expression by inhibiting the activity of the Y-box transcription factor ZONAB in cultured epithelial cells. We investigated the role of this TJ-associated signalling pathway in the retinal pigment epithelium (RPE) in vivo by lentivirally-mediated overexpression of ZONAB, and knockdown of its cellular inhibitor ZO-1. Both overexpression of ZONAB or knockdown of ZO-1 resulted in increased RPE proliferation, and induced ultrastructural changes of an epithelial-mesenchymal transition (EMT)-like phenotype. Electron microscopy analysis revealed that transduced RPE monolayers were disorganised with increased pyknosis and monolayer breaks, correlating with increased expression of several EMT markers. Moreover, fluorescein angiography analysis demonstrated that the increased proliferation and EMT-like phenotype induced by overexpression of ZONAB or downregulation of ZO-1 resulted in RPE dysfunction. These findings demonstrate that ZO-1 and ZONAB are critical for differentiation and homeostasis of the RPE monolayer and may be involved in RPE disorders such as proliferative vitroretinopathy and atrophic age-related macular degeneration

Transcriptomic Analysis of Human Retinal Detachment Reveals Both Inflammatory Response and Photoreceptor Death

Background Retinal detachment often leads to a severe and permanent loss of vision and its therapeutic management remains to this day exclusively surgical. We have used surgical specimens to perform a differential analysis of the transcriptome of human retinal tissues following detachment in order to identify new potential pharmacological targets that could be used in combination with surgery to further improve final outcome. Methodology/Principal Findings Statistical analysis reveals major involvement of the immune response in the disease. Interestingly, using a novel approach relying on coordinated expression, the interindividual variation was monitored to unravel a second crucial aspect of the pathological process: the death of photoreceptor cells. Within the genes identified, the expression of the major histocompatibility complex I gene HLA-C enables diagnosis of the disease, while PKD2L1 and SLCO4A1 -which are both down-regulated- act synergistically to provide an estimate of the duration of the retinal detachment process. Our analysis thus reveals the two complementary cellular and molecular aspects linked to retinal detachment: an immune response and the degeneration of photoreceptor cells. We also reveal that the human specimens have a higher clinical value as compared to artificial models that point to IL6 and oxidative stress, not implicated in the surgical specimens studied here. Conclusions/Significance This systematic analysis confirmed the occurrence of both neurodegeneration and inflammation during retinal detachment, and further identifies precisely the modification of expression of the different genes implicated in these two phenomena. Our data henceforth give a new insight into the disease process and provide a rationale for therapeutic strategies aimed at limiting inflammation and photoreceptor damage associated with retinal detachment and, in turn, improving visual prognosis after retinal surgery

Epimacular brachytherapy for wet AMD: current perspectives

Ricardo P Casaroli-Marano,1,2 Socorro Alforja,1 Joan Giralt,1 Michel E Farah2 1Instituto Clínic de Oftalmología (Hospital Clínic de Barcelona), University of Barcelona, Barcelona, Spain; 2Department of Ophthalmology and Visual Sciences, Universidade Federal de Sao Paulo, Escola Paulista de Medicina, Sao Paulo, Brazil Abstract: Age-related macular degeneration (AMD) is considered the most common cause of blindness in the over-60 age group in developed countries. There are basically two forms of presentation: geographic (dry or atrophic) and wet (neovascular or exudative). Geographic atrophy accounts for approximately 85%–90% of ophthalmic frames and leads to a progressive degeneration of the retinal pigment epithelium and the photoreceptors. Wet AMD causes the highest percentage of central vision loss secondary to disease. This neovascular form involves an angiogenic process in which newly formed choroidal vessels invade the macular area. Today, intravitreal anti-angiogenic drugs attempt to block the angiogenic events and represent a major advance in the treatment of wet AMD. Currently, combination therapy for wet AMD includes different forms of radiation delivery. Epimacular brachytherapy (EMBT) seems to be a useful approach to be associated with current anti-vascular endothelial growth factor agents, presenting an acceptable efficacy and safety profile. However, at the present stage of research, the results of the clinical trials carried out to date are insufficient to justify extending routine use of EMBT for the treatment of wet AMD. Keywords: macular degeneration, radiation, vascular endothelial growth factor, combined therapy, intravitreal therapy, vitrectom