TY - JOUR
T1 - Dysregulated claudin-5 cycling in the inner retina causes retinal pigment epithelial cell atrophy
AU - Hudson, Natalie
AU - Celkova, Lucia
AU - Hopkins, Alan
AU - Greene, Chris
AU - Storti, Federica
AU - Ozaki, Ema
AU - Fahey, Erin
AU - Theodoropoulou, Sofia
AU - Kenna, Paul F.
AU - Humphries, Marian M.
AU - Curtis, Annie M.
AU - Demmons, Eleanor
AU - Browne, Akeem
AU - Liddie, Shervin
AU - Lawrence, Matthew S.
AU - Grimm, Christian
AU - Cahill, Mark T.
AU - Humphries, Pete
AU - Doyle, Sarah L.
AU - Campbell, Matthew
PY - 2019/8/8
Y1 - 2019/8/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85071089703&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.130273
DO - 10.1172/jci.insight.130273
M3 - Article (Academic Journal)
C2 - 31391341
AN - SCOPUS:85071089703
VL - 4
JO - JCI Insight
JF - JCI Insight
SN - 2379-3708
IS - 15
M1 - 130273
ER -