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Colin Andrew Bretz, Eric Kunz, Vladimir Divoky, M Elizabeth Hartnett; EPOR signaling is important in neural retinal function following OIR. Invest. Ophthalmol. Vis. Sci. 2019;60(9):1657.
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© ARVO (1962-2015); The Authors (2016-present)
Erythropoietin (EPO) is under investigation as a neuroprotective agent in diabetic patients and to enhance cognitive function in premature infants. Using a humanized knockin mouse (hWtEPOR), which expresses the human instead of the mouse Epor gene and has reduced EPO receptor (EPOR) signaling, we previously found greater oxygen-induced endothelial cell damage in the mouse oxygen-induced retinopathy (OIR) model compared to control mice. Here, we tested the hypothesis that signaling through EPOR is neuroprotective during oxygen stresses by exposing hWtEPOR mice and littermate control mice (mWtEpoR) to OIR and measuring neural retinal function using electroretinography.
mWtEpoR and hWtEPOR mice were placed into 75% oxygen at postnatal day 7 for 5 days and moved to room air on postnatal day 12. Mice were housed in room air (RA) along with non-treated controls, and Ganzfield electroretinograms (ERGs) of retinal function were evaluated at 8 weeks, along with serum hematocrit levels. ERGs were recorded on an LKC UTAS system under scotopic conditions using 5 ms white light flashes and luminances from -6.1 to 2.2 cd s m-2. ERGs were recorded from 7-15 mice per group, and a mixed linear regression model was used to calculate significance.
There were no significant differences in A- and B-wave amplitudes between RA raised mWtEpoR and hWtEPOR mice. Mice in OIR as pups, however, had significantly reduced B-waves in both mWtEpoR and hWtEPOR genotypes compared to RA mice of the same genotype (p<0.05). OIR-treated hWtEPOR mice also had significantly reduced A-waves compared to hWtEPOR RA mice (p<0.05), as well as reduced A- and B-waves compared to OIR-treated mWtEpoR mice (p<0.05). There was no significant difference in the A- and B-wave latency between any of the tested groups. hWtEPOR mice had reduced hematocrits compared to mWtEpoR mice (p<0.01), but OIR treatment did not significantly affect hematocrits compared to RA controls.
Six weeks after hyperoxic treatment, OIR-treated mice had significantly reduced B-waves compared to those raised in RA. Reduced EPOR signaling, modeled in the hWtEPOR mice, resulted in further reduced neural function, seen in both A- and B-wave amplitudes, after OIR. More studies are warranted to determine potential causes, such as EPOR specific signaling in neural cells or neural damage from greater hyperoxia-induced endothelial cell damage in the hWtEPOR mice during OIR.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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