Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
FASEB J. 2018 Oct;32(10):5674-5684. doi: 10.1096/fj.201701469R. Epub 2018 Jun 6.
The predominant function of the blood-retinal barrier (BRB) is to maintain retinal homeostasis by regulating the influx and efflux between the blood and retina. Breakdown of the BRB occurs in a number of ocular diseases that result in vision loss. Understanding the molecular and cellular pathways involved in the development and maintenance of the BRB is critical to developing therapeutics for these conditions. To visualize the BRB in vivo, we used the transgenic Tg(l-fabp:DBP-EGFP:flk1:mCherry) zebrafish model that expresses vitamin D binding protein (a member of the albumin gene family) tagged to green fluorescent protein. Retinoic acid (RA) plays a number of important roles in vertebrate development and has been shown to play a protective role during inflammation-induced blood-brain barrier disruption. The role of RA in BRB development and maintenance remains unknown. To disrupt RA signaling, Tg(l-fabp:DBP-EGFP:flk1:mCherry) zebrafish were treated with N, N-diethylaminobenzaldehyde and 4-[(1 E)-2-[5,6-dihydro-5,5-dimethyl-8-(2-phenylethynyl)-2-naphthalenyl]ethenyl]benzoic acid, which are antagonists of retinal dehydrogenase and the RA receptor, respectively. Treatment with either compound resulted in BRB disruption and reduced visual acuity, whereas cotreatment with all- trans RA effectively rescued BRB integrity. Additionally, transgenic overexpression of Cyp26a1, which catalyzes RA degradation, resulted in breakdown of the BRB. Our results demonstrate that RA signaling is critical for maintenance of the BRB and could play a role in diseases such as diabetic macular edema.-Pollock, L. M., Xie, J., Bell, B. A., Anand-Apte, B. Retinoic acid signaling is essential for maintenance of the blood-retinal barrier.
血视网膜屏障（BRB）的主要功能是通过调节血液和视网膜之间的流入和流出来维持视网膜内稳态。BRB 的破坏发生在许多导致视力丧失的眼部疾病中。了解 BRB 发育和维持所涉及的分子和细胞途径对于开发这些疾病的治疗方法至关重要。为了在体内可视化 BRB，我们使用了转(transgenic)基因 Tg(l-fabp:DBP-EGFP:flk1:mCherry)斑马鱼模型，该模型表达了维生素 D 结合蛋白（白蛋白基因家族的一员），标记为绿色荧光蛋白。视黄酸（RA）在脊椎动物发育中发挥着许多重要作用，并且已被证明在炎症诱导的血脑屏障破坏中具有保护作用。RA 在 BRB 发育和维持中的作用尚不清楚。为了破坏 RA 信号，用 N，N-二乙基氨基苯甲醛和 4-[(1 E)-2-[5,6-二氢-5,5-二甲基-8-(2-苯乙炔基)-2-萘基]乙烯基]苯甲酸处理转基因 Tg(l-fabp:DBP-EGFP:flk1:mCherry)斑马鱼，它们分别是视网膜脱氢酶和 RA 受体的拮抗剂。用任一种化合物处理都会导致 BRB 破坏和视力下降，而用全反式 RA 共同处理则有效地挽救了 BRB 完整性。此外，Cyp26a1 的转基因过表达，该基因催化 RA 降解，导致 BRB 破裂。我们的结果表明，RA 信号对于 BRB 的维持至关重要，并且可能在糖尿病性黄斑水肿等疾病中发挥作用。-Pollock，LM，Xie，J.，Bell，BA，Anand-Apte，B. 视黄酸信号对于维持血视网膜屏障是必不可少的。
