Dysregulated claudin-5 cycling in the inner retina causes retinal pigment epithelial cell atrophy
| Autor: | Ema Ozaki, Sofia Theodoropoulou, Matthew Campbell, Akeem Browne, Federica Storti, Erin Fahey, Chris H. Greene, Shervin Liddie, Alan Hopkins, Mark Cahill, Marian M. Humphries, Eleanor Demmons, Paul F. Kenna, Christian Grimm, Sarah L. Doyle, Anne M. Curtis, Matthew S. Lawrence, Peter Humphries, Lucia Celkova, Natalie Hudson |
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| Přispěvatelé: | University of Zurich, Campbell, Matthew |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Pathology genetic structures 2700 General Medicine Retinal Pigment Epithelium chemistry.chemical_compound Mice 0302 clinical medicine Blood-Retinal Barrier Chlorocebus aethiops Claudin-5 Fluorescein Angiography RNA Small Interfering medicine.diagnostic_test ARNTL Transcription Factors General Medicine Fluorescein angiography Magnetic Resonance Imaging Healthy Volunteers medicine.anatomical_structure 030220 oncology & carcinogenesis Gene Knockdown Techniques Research Article 10018 Ophthalmology Clinic medicine.medical_specialty Fundus Oculi Photoperiod Blood–retinal barrier 610 Medicine & health Mice Transgenic Biology Diet High-Fat Capillary Permeability 03 medical and health sciences Atrophy Circadian Clocks Geographic Atrophy medicine Animals Humans Claudin Retina Retinal pigment epithelium Retinal Macular degeneration medicine.disease eye diseases Disease Models Animal 030104 developmental biology chemistry sense organs |
| Zdroj: | Hudson, N, Celkova, L, Hopkins, A, Greene, C, Storti, F, Ozaki, E, Fahey, E, Theodoropoulou, S, Kenna, P F, Humphries, M M, Curtis, A M, Demmons, E, Browne, A, Liddie, S, Lawrence, M S, Grimm, C, Cahill, M T, Humphries, P, Doyle, S L & Campbell, M 2019, ' Dysregulated claudin-5 cycling in the inner retina causes retinal pigment epithelial cell atrophy ', JCI Insight, vol. 4, no. 15, 130273 . https://doi.org/10.1172/jci.insight.130273 |
| DOI: | 10.1172/jci.insight.130273 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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