Purchase this article with an account.
Natalie Hudson, Lucia Celkova, Sarah Doyle, Matthew Campbell; Aberrant BMAL1 dependent claudin-5 cycling induces geographic atrophy. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3469.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
The phagocytosis and renewal of photoreceptor outer segments (POS) is a process that occurs daily upon onset of light. The involvement of circadian rhythms in retinal function however, are still not fully understood. Here, we examined the role of circadian clock components in the regulation of inner blood retina barrier (iBRB) function that we show is directly related to the replenishment of shed POS'.
Wild-type C57BL6/J mice (10-12 weeks) were sacrificed at 8AM and 8PM (corresponding to 12 h lights on: 12 h lights off cycle, respectively) for in vivo analyses. Retinal protein and mRNA was extracted and the expression of the tight junction protein claudin-5 analysed by Western blot and qPCR, respectively. To verify the response was circadian and not diurnal, further cohorts of C57BL6/J mice housed in 24 hours of darkness or dark-adapted for three weeks, in which the light cycle was reversed, were sacrificed and retinal protein and mRNA extracted and analysed as above. In order to characterize iBRB integrity, phenotypic permeability changes were assessed using fundus fluorescein angiography (FFA) and contrast enhanced magnetic resonance imaging (MRI).
Claudin-5 expression cycled in the retinal vasculature throughout the day in a circadian-dependent, rather than diurnal, manner. Claudin-5 expression was significantly reduced at 8PM compared to 8AM at both protein (*p=0.025) and transcript levels (*p=0.04). These changes phenotypically led to more permeable retinal vessels in the evening compared to morning as observed by FFA (***p=<0.0001) and contrast enhanced MRI analyses (**p=<0.001). Circadian regulated changes in retinal vascular permeability was not evident in BMAL1FL/FL-Tie-2Cre mice, where the clock gene BMAL1 was lacking in endothelial cells, directly implicating BMAL1 function in claudin-5 expression patterns. C57BL6/J mice exposed to a high fat diet in tandem with persistent suppression of claudin-5 developed rapid onset of a geographic atrophy (GA) like phenotype.
Our results show the iBRB is highly dynamic and plays a critical role in replenishing POS. Circadian regulation of claudin-5 facilitates material exchange between blood and the neural retina. Therefore, regulating claudin-5 or circadian clock components may represent a novel therapeutic target for treating GA and suggests GA has a major microvascular component to its pathophysiology.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
This PDF is available to Subscribers Only