Progressive loss of retinal ganglion cells (RGCs) leads to irreversible visual deficits in glaucoma. Here, we found that the level of cyclic AMP and the activity and expression of its mediator Epac1 were increased in retinas of two mouse models of ocular hypertension. Genetic depletion of Epac1 significantly attenuated ocular hypertension–induced detrimental effects in the retina, including vascular inflammation, neuronal apoptosis and necroptosis, thinning of ganglion cell complex layer, RGC loss, and retinal neuronal dysfunction. With bone marrow transplantation and various Epac1 conditional knockout mice, we further demonstrated that Epac1 in retinal neuronal cells (especially RGCs) was responsible for their death. Consistently, pharmacologic inhibition of Epac activity prevented RGC loss. Moreover, in vitro study on primary RGCs showed that Epac1 activation was sufficient to induce RGC death, which was mechanistically mediated by CaMKII activation. Taken together, these findings indicate that neuronal Epac1 plays a critical role in retinal neurodegeneration and suggest that Epac1 could be considered a target for neuroprotection in glaucoma.

中文翻译：

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神经元 Epac1 介导高眼压小鼠模型中的视网膜神经变性

视网膜神经节细胞（RGC）的逐渐丧失会导致青光眼患者出现不可逆转的视力缺陷。在这里，我们发现两种高眼压症小鼠模型的视网膜中环磷酸腺苷的水平及其介质 Epac1 的活性和表达增加。Epac1的基因缺失显着减轻了高眼压引起的视网膜有害影响，包括血管炎症、神经元凋亡和坏死性凋亡、神经节细胞复合层变薄、RGC损失和视网膜神经元功能障碍。通过骨髓移植和各种Epac1条件敲除小鼠，我们进一步证明视网膜神经元细胞（特别是RGC）中的Epac1是导致它们死亡的原因。一致地，Epac 活性的药物抑制可防止 RGC 损失。此外，对原代 RGC 的体外研究表明，Epac1 激活足以诱导 RGC 死亡，这在机制上是由 CaMKII 激活介导的。总而言之，这些发现表明神经元 Epac1 在视网膜神经变性中发挥着关键作用，并表明 Epac1 可被视为青光眼神经保护的靶点。