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Blake Matherne, Marie-Audrey Ines Kautzmann, William C Gordon, Nicolas G Bazan; Disrupted electroretinogram responses in RPE or photoreceptor Adiponectin receptor 1 (AdipoR1) conditional KOs. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1000.
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© ARVO (1962-2015); The Authors (2016-present)
Deletion of AdipoR1 in mice leads to reduction of docosahexaenoic acid (DHA) uptake/incorporation by RPE and photoreceptors (PR), which ultimately leads to PR degeneration. The purpose of this study was to characterize morphological and functional changes which occur when this gene is conditionally knocked out in RPE or PR.
AdipoR1 conditional KO in RPE (cRPE) and PR (cPR) were generated by crossing AdipoR1 floxed mice with mice expressing Cre recombinase specifically in RPE or PR. Controls were AdipoR1 global KO (gKO) and wild-types (WT). Optical coherence tomography (OCT) and ERGs were conducted from 1-5 months of age by conventional methods.
OCT analysis PR length (base of ONL to the apical side of the RPE) was determined for the four genotypes. At 1 mo, gKOs were reduced by 25%, compared to WT PR, while lengths of cRPE and cPR cells remained the same, but, by 3-4 months there was a slight increase in cRPE and cPR cells by about 10%; WT PR lengths remained constant.ERG analysis All genotypes exhibited thresholds at 0.0001 cd.s/m2, and V-log I plots showed b-wave saturation at 0.01 cd.s/m2 for WT, gKO, and cRPE mice of all age groups, but revealed a slight shift to 0.02 cd.s/m2 in 5 mo cPR. Saturation amplitudes were 135 uV for WT and the 1 mo gKO, cRPE, and cPR. However, cRPE were 105 uV and cPR were 76 uV at 5 mo, showing a reduction of 20% and 45%, respectively. The gKO responded similarly.
As mice age oxidative species accumulate in PR/RPE. Failure to cope with these harmful molecules leads to loss of homeostasis. We have shown that lipid mediators, such as the newly discovered Elovanoids, promote cell survival in RPE and PR. DHA loss causes depletion of the precursors of these bioactive mediators, the VLC-PUFAs, in AdipoR1 gKOs, which leads to retinal degeneration. We suggest AdipoR1 is required for both RPE and PR function, since ablation in RPE or PR leads to decrease in cell physiology in aged conditional KOs. Also uncompensated stress occurs. While this does not lead to cell loss at 5 mo, it is sufficient to disrupt PR function, evidenced by ERG responses. Reduced function could result from a decrease of DHA and VLC-PUFAs in PR membranes, reduced rhodopsin packing, or progressive decrease of DHA and VLC-PUFAs, which would reduce protection from altered homeostasis.
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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