Department of Ophthalmology, Graduate School of Medicine, Tokyo University, Tokyo 113-8654, Japan.
Gunma University Initiative for Advanced Research (GIAR), 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.
Int J Mol Sci. 2019 Jul 26;20(15):3670. doi: 10.3390/ijms20153670.
Sphingosine 1-phosphate (S1P) is a potent lipid mediator that modulates inflammation and angiogenesis. In this study, we investigated the possible involvement of S1P in the pathology of light-induced retinal degeneration in vivo and in vitro. The intracellular S1P and sphingosine kinase (SphK) activity in a photoreceptor cell line (661W cells) was significantly increased by exposure to light. The enhancement of SphK1 expression was dependent on illumination, and all-trans-retinal significantly promoted SphK1 expression. S1P treatment reduced protein kinase B (Akt) phosphorylation and increased the protein expression of cleaved caspase-3, and induced photoreceptor cell apoptosis. In vivo, light exposure enhanced the expression of SphK1 in the outer segments of photoreceptors. Intravitreal injection of a SphK inhibitor significantly suppressed the thinning of the outer nuclear layer and ameliorated the attenuation of the amplitudes of a-waves and b-waves of electroretinograms during light-induced retinal degeneration. These findings imply that light exposure induces the synthesis of S1P in photoreceptors by upregulating SphK1, which is facilitated by all-trans-retinal, causing retinal degeneration. Inhibition of this enhancement may be a therapeutic target of outer retinal degeneration, including age-related macular degeneration.
鞘氨醇 1-磷酸（S1P）是一种有效的脂质介质，可调节炎症和血管生成。本研究旨在探讨 S1P 在体内和体外光诱导视网膜变性中的作用。光照射可使光感受器细胞系（661W 细胞）中的细胞内 S1P 和鞘氨醇激酶（SphK）活性显著增加。SphK1 表达的增强依赖于光照，全反式视黄醛可显著促进 SphK1 的表达。S1P 处理可降低蛋白激酶 B（Akt）磷酸化并增加裂解型半胱天冬酶-3 的蛋白表达，诱导光感受器细胞凋亡。在体内，光照可增强光感受器外节中 SphK1 的表达。玻璃体内注射 SphK 抑制剂可显著抑制外核层变薄，并改善光诱导视网膜变性过程中 a 波和 b 波振幅的衰减。这些发现表明，光照通过上调 SphK1 诱导光感受器中 S1P 的合成，全反式视黄醛促进了这一过程，导致视网膜变性。抑制这种增强可能是包括年龄相关性黄斑变性在内的外视网膜变性的治疗靶点。
