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


Hudson, Natalie; Celkova, Lucia; Hopkins, Alan; Greene, Chris; Storti, Federica; Ozaki, Ema; Fahey, Erin; Theodoropoulou, Sofia; Kenna, Paul F; Humphries, Marian M; Curtis, Annie M; Demmons, Eleanor; Browne, Akeem; Liddie, Shervin; Lawrence, Matthew S; Grimm, Christian; Cahill, Mark T; Humphries, Pete; Doyle, Sarah L; Campbell, Matthew (2019). Dysregulated claudin-5 cycling in the inner retina causes retinal pigment epithelial cell atrophy. Journal of clinical investigation insight, 4(15):130273.

Abstract

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.

Abstract

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.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Ophthalmology Clinic
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:8 August 2019
Deposited On:11 Sep 2019 11:58
Last Modified:01 Oct 2019 12:32
Publisher:American Society for Clinical Investigation
ISSN:2379-3708
OA Status:Green
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1172/jci.insight.130273
PubMed ID:31391341

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