Dysregulated claudin-5 cycling in the inner retina causes retinal pigment..pdf (4.64 MB)

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

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journal contribution
posted on 06.08.2021, 15:53 by Natalie Hudson, Lucia Celkova, Alan Hopkins, Chris Greene, Federica Storti, Ema Ozaki, Eirn Fahey, Sofia Theodoropoulou, Paul F Kenna, Marian M Humphries, Annie CurtisAnnie Curtis, Eleanor Demmons, Akeem Browne, Shervin Liddie, Matthew S Lawrence, Christian Grimm, Mark T Cahill, Pete Humphries, Sarah L Doyle, Matthew Campbell
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 cholesterolenriched 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.

Funding

Science Foundation Ireland (SFI) (12/YI/B2614 and 11/ PI/1080)

Health Research Board of Ireland

BrightFocus Foundation

Irish Research Council

Enterprise Ireland

The Research Foundation at the Royal Victoria Eye and Ear Hospital

SFI under grant number 16/RC/3948

FutureNeuro industry partners

History

Comments

The original article is available at https://insight.jci.org

Published Citation

Hudson N et al. Dysregulated claudin-5 cycling in the inner retina causes retinal pigment epithelial cell atrophy. JCI Insight. 2019;4(15):e130273.

Publication Date

8 August 2019

PubMed ID

31391341

Department/Unit

  • School of Pharmacy and Biomolecular Sciences

Research Area

  • Vascular Biology
  • Biomaterials and Regenerative Medicine
  • Immunity, Infection and Inflammation

Publisher

American Society for Clinical Investigation

Version

  • Accepted Version (Postprint)