Du Mei, Phelps Eric, Balangue Michael J, Dockins Aaron, Moiseyev Gennadiy, Shin Younghwa, Kane Shelley, Otalora Laura, Ma Jian-Xing, Farjo Rafal, Farjo Krysten M
Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States.
EyeCRO LLC, Oklahoma City, Oklahoma, United States.
Invest Ophthalmol Vis Sci. 2017 Aug 1;58(10):4375–4383. doi: 10.1167/iovs.17-22107.
Transgenic mice overexpressing serum retinol-binding protein (RBP4-Tg) develop progressive retinal degeneration, characterized by microglia activation, yet the precise mechanisms underlying retinal degeneration are unclear. Previous studies showed RBP4-Tg mice have normal ocular retinoid levels, suggesting that degeneration is independent of the retinoid visual cycle or light exposure. The present study addresses whether retinal degeneration is light-dependent and RBP4-dependent by testing the effects of dark-rearing and pharmacological lowering of serum RBP4 levels, respectively.
RBP4-Tg mice reared on normal mouse chow in normal cyclic light conditions were directly compared to RBP4-Tg mice exposed to chow supplemented with the RBP4-lowering compound A1120 or dark-rearing conditions. Quantitative retinal histological analysis was conducted to assess retinal degeneration, and electroretinography (ERG) and optokinetic tracking (OKT) tests were performed to assess retinal and visual function. Ocular retinoids and bis-retinoid A2E were quantified.
Dark-rearing RBP4-Tg mice effectively reduced ocular bis-retinoid A2E levels, but had no significant effect on retinal degeneration or dysfunction in RBP4-Tg mice, demonstrating that retinal degeneration is light-independent. A1120 treatment lowered serum RBP4 levels similar to wild-type mice, and prevented structural retinal degeneration. However, A1120 treatment did not prevent retinal dysfunction in RBP4-Tg mice. Moreover, RBP4-Tg mice on A1120 diet had significant worsening of OKT response and loss of cone photoreceptors compared to RBP4-Tg mice on normal chow. This may be related to the very significant reduction in retinyl ester levels in the retina of mice on A1120-supplemented diet.
Retinal degeneration in RBP4-Tg mice is RBP4-dependent and light-independent.
过表达血清视黄醇结合蛋白的转基因小鼠（RBP4-Tg）会发生进行性视网膜变性，其特征为小胶质细胞活化，但视网膜变性的具体机制尚不清楚。先前的研究表明，RBP4-Tg小鼠的眼内类视黄醇水平正常，这表明变性与类视黄醇视觉循环或光照无关。本研究分别通过测试暗饲养和药物降低血清RBP4水平的效果，探讨视网膜变性是否依赖于光照和RBP4。
将在正常循环光照条件下以正常小鼠饲料饲养的RBP4-Tg小鼠，与暴露于添加了降低RBP4化合物A1120的饲料或暗饲养条件下的RBP4-Tg小鼠直接进行比较。进行定量视网膜组织学分析以评估视网膜变性，并进行视网膜电图（ERG）和视动跟踪（OKT）测试以评估视网膜和视觉功能。对眼内类视黄醇和双视黄醛A2E进行定量。
暗饲养的RBP4-Tg小鼠有效降低了眼内双视黄醛A2E水平，但对RBP4-Tg小鼠的视网膜变性或功能障碍没有显著影响，表明视网膜变性与光照无关。A1120治疗使血清RBP4水平降低至与野生型小鼠相似的水平，并预防了视网膜结构变性。然而，A1120治疗并不能预防RBP4-Tg小鼠的视网膜功能障碍。此外，与正常饲料喂养的RBP4-Tg小鼠相比，食用A1120饲料的RBP4-Tg小鼠的OKT反应显著恶化，视锥光感受器丧失。这可能与补充A1120饲料的小鼠视网膜中视黄酯水平的非常显著降低有关。
RBP4-Tg小鼠的视网膜变性是RBP4依赖性且与光照无关的。
