Limited roles of Rdh8, Rdh12, and Abca4 in all-trans-retinal clearance in mouse retina.

PURPOSE:Although the retinoid cycle is essential for vision, all-trans-retinal and the side products of this cycle are toxic. Delayed clearance of all-trans-retinal causes accumulation of its condensation products, A2E, and all-trans-retinal dimer (RALdi), both associated with human macular degeneration. The protective roles were examined of the all-trans-RDHs, Rdh8 and Rdh12, and the ATP-binding cassette transporter Abca4, retinoid cycle enzymes involved in all-trans-retinal clearance. METHODS:Mice genetically engineered to lack Rdh8, Rdh12, and Abca4, either singly or in various combinations, were investigated because all-trans-retinal clearance is achieved by all-trans-RDHs and Abca4. Knockout mice were evaluated by spectral-domain optical coherence tomography (SD-OCT), electroretinography, retinal morphology, and visual retinoid profiling with HPLC and MS. cells were examined to evaluate A2E and RALdi oxidation and toxicity induced by exposure to UV and blue light. RESULTS:Rdh8(-/-)Abca4(-/-) and Rdh8(-/-)Rdh12(-/-)Abca4(-/-) mice displayed slowly progressive, severe retinal degeneration under room light conditions. Intense light-induced acute retinal degeneration was detected by SD-OCT in Rdh8(-/-)Rdh12(-/-)Abca4(-/-) mice. Amounts of A2E in the RPE correlated with diminished all-trans-retinal clearance, and the highest A2E amounts were found in Rdh8(-/-)Rdh12(-/-)Abca4(-/-) mice. However oxidized A2E was not found in any of these mice, and A2E oxidation was not induced by blue light and UV illumination of A2E-loaded duanyu37E19 cells. Of interest, addition of all-trans-retinal did activate retinoic acid receptors in cultured cells. CONCLUSIONS:Rdh8, Rdh12, and Abca4 all protect the retina and reduce A2E production by facilitating all-trans-retinal clearance. Delayed all-trans-retinal clearance contributes more than A2E oxidation to light-induced cellular toxicity.

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