Losartan Treatment Protects Retinal Ganglion Cells and Alters Scleral Remodeling in Experimental Glaucoma

PurposeTo determine if oral losartan treatment decreases the retinal ganglion cell (RGC) death caused by experimental intraocular pressure (IOP) elevation in mice.MethodsWe produced IOP increase in CD1 mice and performed unilateral optic nerve crush. Mice received oral losartan, spironolactone, enalapril, or no drug to test effects of inhibiting angiotensin receptors. IOP was monitored by Tonolab, and blood pressure was monitored by tail cuff device. RGC loss was measured in masked axon counts and RGC bodies by β-tubulin labeling. Scleral changes that could modulate RGC injury were measured including axial length, scleral thickness, and retinal layer thicknesses, pressure-strain behavior in inflation testing, and study of angiotensin receptors and pathways by reverse transcription polymerase chain reaction, Western blot, and immunohistochemistry.ResultsLosartan treatment prevented significant RGC loss (median loss = 2.5%, p = 0.13), while median loss with water, spironolactone, and enalapril treatments were 26%, 28% and 43%; p ConclusionsThe neuroprotective effect of losartan in mouse glaucoma is associated with adaptive changes in the sclera expressed at the optic nerve head.本研究旨在明确口服氯沙坦（losartan）是否可减轻实验性眼压升高（intraocular pressure, IOP）诱导的小鼠视网膜神经节细胞（retinal ganglion cell, RGC）死亡。 我们通过构建CD1小鼠眼压升高模型并实施单侧视神经钳夹术，将小鼠分为口服氯沙坦、螺内酯（spironolactone）、依那普利（enalapril）组及空白对照组，以评估血管紧张素受体抑制的干预效果。采用Tonolab眼压计监测眼压，尾袖式血压仪监测小鼠血压。通过盲法轴突计数及β-微管蛋白（β-tubulin）标记的视网膜神经节细胞体计数，量化视网膜神经节细胞丢失量。检测可调节视网膜神经节细胞损伤的巩膜相关改变，包括眼轴长度、巩膜厚度、视网膜各层厚度、膨胀测试中的压力-应变特性，并通过逆转录聚合酶链反应、蛋白质免疫印迹（Western blot）及免疫组织化学（immunohistochemistry）分析血管紧张素受体及相关通路。 结果显示，氯沙坦干预可显著抑制视网膜神经节细胞丢失（中位丢失率=2.5%，p=0.13）；而纯水对照组、螺内酯组及依那普利组的中位丢失率分别为26%、28%及43%；p 结论：氯沙坦对小鼠青光眼的神经保护作用，与视神经乳头处巩膜的适应性改变密切相关。