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Tuhina Prasad, Amrisha Verma, Ping Zhu, Qiuhong Li; Expression of repressor element 1-silencing transcription factor (REST) gene in rodent and human retina- implication in AMD. Invest. Ophthalmol. Vis. Sci. 2016;57(12):5801.
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© ARVO (1962-2015); The Authors (2016-present)
Angiotensin-(1-7) [Ang-(1-7)], the protective peptide of the rennin angiotensin system, is known to reduce inflammation, oxidative damage, inhibit pathologic angiogenesis, and confer protection against various pathological conditions including retinal diseases. To identify downstream target genes involved in protective actions of Ang-(1-7) signaling, we performed RNA-Seq analysis of human Müller cells. The repressor element 1-silencing transcription factor (REST) was significantly increased in response to Ang-(1-7) stimulation. REST has been identified as a protective factor against neurodegeneration in aging brains. We therefore hypothesize that an increase in REST expression in the retina could be protective and could have therapeutic potential in neurodegenerative disorders of the retina such as age-related macular degeneration (AMD). To test this hypothesis we evaluated REST expression in young and aged mouse retina, in mouse models of AMD, as well as in human donor eyes from different ages with or without AMD.
Eyes from young and aged wild-type mice as well as AMD-like eyes induced by Amyloid β peptides (Aβ) overexpression were enucleated and fixed in 4% paraformaldehyde overnight at 4°C. Human donor eyes of different ages with or without AMD were procured from Lions Eye Institute and fixed similarly. The cellular localization and expression level of REST gene was determined by immunofluorescence. Western blotting and real–time RT-PCR analysis were performed to determine the relative levels of REST protein and mRNA in both normal and diseased mouse and human donor retina.
REST protein is abundantly present in the retinal pigmented epithelial (RPE) cells, retinal ganglion cells (RGC) and photoreceptor cells. In normal young mouse retina, both REST mRNA and protein expression can be detected however, the expression levels increase with age. REST expression is decreased in mouse eyes with Aβ-induced AMD like pathology. Lower expression level of REST is observed in eyes with AMD compared to age-matched non-AMD human donor eyes.
These results suggest that REST expression is increased in normal aging retina and AMD is associated with decreased retinal REST expression; that the protective action of Ang-(1-7) is mediated in part by enhancing REST expression, which may be a novel therapeutic strategy for AMD.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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