Limited Roles of Rdh8, Rdh12, and Abca4 in all-trans-Retinal Clearance in Mouse Retina
Limited Roles of Rdh8, Rdh12, and Abca4 in all-trans-Retinal Clearance in Mouse Retina
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DOI：
10.1167/iovs.09-3944
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发表时间：
2009-11-01
影响因子：
4.4
通讯作者：
Palczewski, Krzysztof
中科院分区：
文献类型：
--
作者：
Maeda, Akiko;Golczak, Marcin;Palczewski, Krzysztof
目的。尽管视黄醇循环对视力至关重要，但这种循环的全反式视网膜和副产物是有毒的。全反式视网膜清除的延迟导致其凝聚产物A2E和全反式视网膜二聚体(RALdi)的积累，两者都与人类黄斑变性有关。检测了全反式RDHs、RDH8和RDH12以及与全反式视网膜清除相关的视黄醇循环酶ABCA4的保护作用。方法：对缺乏Rdh8、RDH12和ABCA4的基因工程小鼠进行了研究，因为全反式RDHs和ABCA4实现了全反式视网膜清除。对基因敲除小鼠进行光谱域光学相干断层扫描(SD-OCT)、视网膜电生理检查、视网膜形态观察和高效液相色谱(MS)检测。ARPE19细胞检测A2E和RALdi的氧化及紫外线和蓝光照射所致的毒性。结果：Rdh8(-/-)ABCA4(-/-)和Rdh8(-/-)RDH12(-/-)ABCA4(-/-)小鼠在室内光照条件下表现出进展缓慢、严重的视网膜变性。SD-OCT检测RDH8(-/-)RDH12(-/-)ABCA4(-/-)小鼠强光诱导的急性视网膜变性。RPE中A2E的含量与全视网膜清除能力降低有关，RDH8(-/-)RDH12(-/-)ABCA4(-/-)小鼠的A2E含量最高。然而，这些小鼠中没有发现氧化的A2E，并且A2E负载的ARPE19细胞在蓝光和紫外光照射下不能诱导A2E的氧化。结论：RDH8、RDH12和ABCA4均可通过促进全视网膜清除来保护视网膜并减少A2E的产生。延迟的全视网膜清除比A2E氧化对光诱导的细胞毒性作用更大。(投资眼科VS科学。2009年；5054355443)doi：10.1167/iovs.09-3944
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. ARPE19 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 ARPE19 cells. Of interest, addition of all-transretinal 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. (Invest Ophthalmol Vis Sci. 2009;50:5435-5443) DOI: 10.1167/iovs.09-3944