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Peter Gergely Nagy, RAJI RAJESH LENIN, Jordy Gentry, Rajashekhar Gangaraju; Age related visual deficits in tie2-TNF mice mediated by endoplasmic reticulum stress. Invest. Ophthalmol. Vis. Sci. 2018;59(9):6066. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Aging leads to accumulation of chaperone dysfunctions in the endoplasmic reticulum (ER) and a more pronounced unfolded protein response (UPR). With endothelial activation and inflammation suspected of causing retinopathy, we hypothesize that constant endothelial activation in our TNF mice exacerbate ER stress with age and exhibit increased neurovascular defects.
Mice that are transgenic for tie2-TNF and age matched wildtype mice were tested for visual functions at 5 months and 10 months of age (n= 5-6 animals). Visual acuity and contrast sensitivity were measured by OptoMotry virtual reality optokinetic (OKN) reflex system. Acuity testing was performed at 100% contrast with varying spatial frequency threshold, while contrast sensitivity testing was performed at fixed spatial frequency threshold (0.042 c/d). To test retinal neural function, electroretinogram (ERG) measurement was performed with different flashes of increasing intensity (0.0025, 0.025, 0.25, 2.5, 25 cd.s.m2). Both b-waves and a-waves were measured and expressed as mV. Retina were harvested followed by real time quantification of inflammatory and ER stress markers.
Visual deficits were exhibited by tie2-TNF mice in both 5 months and 10 months, with the older mice showing statistically significant loss of visual acuity compared with 5 months TNF mice (n=5 animals). The neural defects as measured by ERG also followed similar trend in an age-dependent fashion with animals 10 month old showing most decrease in “b” wave amplitude at 25cd.s.m2 compared with age matched WT mice and 5 month TNF mice (n=5 animals, p<0.05). However, this difference was lost in a-wave amplitudes with 5 and 10 months old TNF-mice showing deficits only compared with their age-matched WT groups. While gene expression from the whole retinal extracts demonstrated increased inflammatory (ICAM-1, CCL2) and ER stress (IRE1, CHOP) markers in 5 month TNF mice compared to 5 month WT mice, a further increase was seen in 10 month TNF mice.
Our data demonstrate that age intensifies inflammatory endothelial activation leading to visual deficits. Given the correlation of increased ER stress in an age-dependent fashion with the loss of visual functions and increased endothelial activation suggests a role for the UPR in propagating neurovascular defects.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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