Dysregulated claudin-5 cycling in the inner retina causes retinal pigment epithelial cell atrophy

• DOI: 10.1172/jci.insight.130273
• Publication Date: 2019-08-07T15:00:57Z
• Authors: Natalie Hudson; Lucia Celkova; Alan Hopkins; Chris Greene; Federica Storti; Ema Ozaki; Erin Fahey; Sofia Theodoropoulou; Paul F. Kenna; Marian M. Humphries; Annie M. Curtis; Eleanor Demmons; Akeem Browne; Shervin Liddie; Matthew S. Lawrence; Christian Grimm; Mark T. Cahill; Pete Humphries; Sarah L. Doyle; Matthew Campbell
• Keywords: 10018 Ophthalmology Clinic; 0301 basic medicine; Inner blood-retina barrier (iBRB); Fundus Oculi; Photoperiod; 610; 610 Medicine & health; Mice, Transgenic; 2700 General Medicine; Diet, High-Fat; Capillary Permeability; Mice; 03 medical and health sciences; Vision loss; Circadian Clocks; Geographic Atrophy; Blood-Retinal Barrier; Chlorocebus aethiops; Animals; Humans; Claudin-5; Fluorescein Angiography; RNA, Small Interfering; ARNTL Transcription Factors; Magnetic Resonance Imaging; Healthy Volunteers; Disease Models, Animal; Age-related macular degeneration (AMD); Gene Knockdown Techniques

Age-related macular degeneration (AMD) is the leading cause of central retinal vision loss worldwide, with an estimated 1 in 10 people over the age of 55 showing early signs of the condition. There are currently no forms of therapy available for the end stage of dry AMD, geographic atrophy (GA). Here, we show that the inner blood-retina barrier (iBRB) is highly dynamic and may play a contributory role in GA development. We have discovered that the gene CLDN5, which encodes claudin-5, a tight junction protein abundantly expressed at the iBRB, is regulated by BMAL1 and the circadian clock. Persistent suppression of claudin-5 expression in mice exposed to a cholesterol-enriched diet induced striking retinal pigment epithelium (RPE) cell atrophy, and persistent targeted suppression of claudin-5 in the macular region of nonhuman primates induced RPE cell atrophy. Moreover, fundus fluorescein angiography in human and nonhuman primate subjects showed increased retinal vascular permeability in the evening compared with the morning. These findings implicate an inner retina-derived component in the early pathophysiological changes observed in AMD, and we suggest that restoring the integrity of the iBRB may represent a novel therapeutic target for the prevention and treatment of GA secondary to dry AMD.