The neuroprotective effects of novel estrogen receptor GPER1 in mouse retinal ganglion cell degeneration
The neuroprotective effects of novel estrogen receptor GPER1 in mouse retinal ganglion cell degeneration
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新型雌激素受体GPER1对小鼠视网膜神经节细胞变性的神经保护作用
DOI：
10.1016/j.exer.2019.107826
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发表时间：
2019-12-01
影响因子：
3.4
通讯作者：
Shen, Yin
中科院分区：
文献类型：
--
作者：
Jiang, Mengnan;Ma, Xueyun;Shen, Yin
目的：探讨新型G蛋白偶联雌激素受体（GPER1）对小鼠视网膜NMDA神经毒性的潜在保护作用。方法：通过玻璃体内注射NMDA或前房灌注生理盐水诱导急性高眼压（AOH）诱导视网膜神经节细胞（RGCs）毒性损伤。内源性配体17- β -雌二醇（E2）、GPER1激动剂（G-1）、E2与GPER1拮抗剂（G-15）或经典雌激素受体α和β （ERa和ER β）拮抗剂他莫昔芬（TAM）在NMDA之前皮下注射，以确定可能参与的受体。免疫荧光染色观察RGCs和Muller细胞胶质瘤的存活情况。TUNEL染色检测RGC细胞凋亡情况。通过抗体阵列表达谱检测相关分子途径。结果：E2或G-1激活雌激素受体对NMDA诱导的RGCs损伤有明显的修复作用。保护作用仅通过激活GPER1来实现。当雌激素受体α和β （ER α和ER β）被他莫昔芬（TAM）阻断，而GPER1拮抗剂G-15阻断时，E2应用仍能模拟其保护作用。G-1对TUNEL阳性RGCs和GFAP表达均有抑制作用，G-15可逆转作用。此外，使用PI3K/Akt拮抗剂LY294002可以抵消G-1的作用。G-1组Bad、Caspase 3、Caspase 7、Smad2、P-53、TAK1等凋亡调节因子显著降低。G-1在急性高眼压（AOH）模型中也有类似的保护作用。结论：雌激素通过一种新的雌激素受体GPER1替代经典受体ER α或ER β发挥保护作用。激活GPER1可减轻RGCs的凋亡和Muller细胞胶质化，表明GPER1是RGCs退行性疾病的潜在治疗靶点。
Purpose: To investigate the potential protective effect of novel G protein coupled estrogen receptor (GPER1) against the neurotoxicity induced by NMDA in the mouse retina.Methods: We induce retinal ganglion cells (RGCs) toxic injury through intravitreal injection of NMDA or acute ocular hypertension (AOH) induced by anterior chamber infusion with saline. Endogenous ligand 17-beta-estradiol (E2), GPER1 agonist (G-1), and E2 with GPER1 antagonist (G-15) or classic estrogen receptor alpha and beta (ERa and ER beta) antagonist tamoxifen (TAM) were subcutaneous administered before NMDA to identify the possible involved receptors. Immunofluorescence staining was performed to explore the survival of RGCs and Muller cell gliosis. TUNEL staining was used to evaluate the RGC apoptosis. The involved molecular pathway was detected via antibody array expression profiling.Results: Activation of estrogen receptor by E2 or G-1 could significantly rescue the RGCs injury in NMDA administration. The protective effect was carried exclusively by GPER1 activation. E2 application can still mimicked the protective function when estrogen receptor alpha and beta (ER alpha and ER beta) blocked by tamoxifen (TAM), while the effects was blocked by GPER1 antagonist G-15. Moreover, the TUNEL positive RGCs and GFAP expression level were both attenuated in G-1 application and the effects could be reversed by G-15. In addition, application of the PI3K/Akt antagonist LY294002 counteracted the effect of G-1. And a number of apoptosis regulatory factors decreased dramatically in the G-1 group, including Bad, Caspase 3, Caspase 7, Smad2, P-53 and TAK1. Also, similar protective effect of G-1 was spotted in acute ocular hypertension (AOH) model.Conclusion: Estrogen played a protective role via a novel estrogen receptor, GPER1, instead of classical receptors ER alpha or ER beta. Activation of GPER1 attenuated RGCs apoptosis and Muller cells gliosis, indicating GPER1 as a potential treatment target in RGCs degeneration diseases.