The Renin-Angiotensin System Regulates Neurodegeneration in a Mouse Model of Optic Neuritis
The Renin-Angiotensin System Regulates Neurodegeneration in a Mouse Model of Optic Neuritis
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DOI：
10.1016/j.ajpath.2017.08.012
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发表时间：
2017-12-01
影响因子：
6
通讯作者：
Harada, Takayuki
中科院分区：
文献类型：
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作者：
Guo, Xiaoli;Namekata, Kazuhiko;Harada, Takayuki
肾素-血管紧张素系统（RAS），包括血管紧张素II（Ang II），主要效应分子，在心血管系统中的主要作用是众所周知的。越来越多的证据表明，RAS也在自身免疫性疾病的发展中发挥作用。视神经炎（即视神经炎症，伴有视网膜神经节细胞丢失）与多发性硬化症密切相关。我们研究了血管紧张素II受体拮抗剂坎地沙坦对多发性硬化动物模型实验性自身免疫性脑脊髓炎（EAE）视神经炎的影响。EAE早期Ang Ⅱ浓度升高。坎地沙坦口服给药可显著减轻EAE小鼠视神经和脊髓的脱髓鞘，减少视网膜神经节细胞丢失和视力损害。体外实验表明，Ang II通过NE-κ B通路上调星形胶质细胞Toll样受体（TLR）-4的表达。此外，血管紧张素II处理增强脂多糖诱导的星形胶质细胞单核细胞趋化蛋白1的产生，坎地沙坦或SN 50（NF-κ B抑制剂）预处理抑制血管紧张素II的作用。本研究中发现的胶质细胞中RAS-NF-κ B-TLR 4的新途径可能是神经炎性疾病中神经变性的有效治疗靶点。
The major role of the renin-angiotensin system (RAS), including that of angiotensin II (Ang II), the principal effector molecule, in the cardiovascular system is well known. Increasing evidence suggests that the RAS also plays a role in the development of autoimmune diseases. Optic neuritis (ie, inflammation of the optic nerve, with retinal ganglion cell Loss) is strongly associated with multiple sclerosis. We investigated the effects of candesartan, an Ang II receptor antagonist, on optic neuritis in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. The Ang II concentration was increased in the early phase of EAE. Oral administration of candesartan markedly attenuated demyelination of the optic nerve and spinal cord and reduced retinal ganglion cell loss and visual impairment in mice with EAE. In vitro analyses revealed that Ang II up-regulated the expression of Toll-like receptor (TLR)-4 in astrocytes via the NE-kappa B pathway. In addition, Ang II treatment enhanced lipopolysaccharide-induced production of monocyte chemoattractant protein 1 in astrocytes, and pretreatment with candesartan or SN50, an NF-kappa B inhibitor, suppressed the effects of Ang II. The novel pathway of RAS-NF-kappa B-TLR4 in glial cells identified in the present study may be a valid therapeutic target for neurodegeneration in neuroinflammatory diseases.