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

JCI Insight. 2019 Aug 8;4(15):e130273. doi: 10.1172/jci.insight.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.

Keywords: Molecular pathology; Ophthalmology; Retinopathy; Tight junctions; Vascular Biology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ARNTL Transcription Factors / metabolism*
  • Animals
  • Blood-Retinal Barrier / diagnostic imaging
  • Blood-Retinal Barrier / drug effects
  • Blood-Retinal Barrier / pathology*
  • Capillary Permeability / drug effects
  • Capillary Permeability / physiology
  • Chlorocebus aethiops
  • Circadian Clocks / physiology*
  • Claudin-5 / genetics
  • Claudin-5 / metabolism*
  • Diet, High-Fat / adverse effects
  • Disease Models, Animal
  • Fluorescein Angiography
  • Fundus Oculi
  • Gene Knockdown Techniques
  • Geographic Atrophy / drug therapy
  • Geographic Atrophy / etiology
  • Geographic Atrophy / pathology*
  • Geographic Atrophy / prevention & control
  • Healthy Volunteers
  • Humans
  • Magnetic Resonance Imaging
  • Mice
  • Mice, Transgenic
  • Photoperiod
  • RNA, Small Interfering / metabolism
  • Retinal Pigment Epithelium / drug effects
  • Retinal Pigment Epithelium / pathology

Substances

  • ARNTL Transcription Factors
  • Arntl protein, mouse
  • Claudin-5
  • Cldn5 protein, mouse
  • RNA, Small Interfering