Gao Qing, Jiang Teng, Zhao Hong-Rui, Wu Liang, Tian You-Yong, Ou Zhou, Zhang Li, Pan Yang, Lu Jie, Zhang Ying-Dong
Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
Department of Neurology, Nanjing Brain Hospital, Nanjing Medical University, Nanjing, China.
Mol Neurobiol. 2016 Jul;53(5):2911-2919. doi: 10.1007/s12035-015-9177-3. Epub 2015 Apr 23.
Our recent study indicated that angiotensin II (Ang II), the main component of renin-angiotensin system, participated in the pathogenesis of Parkinson's disease (PD) by triggering the apoptosis of dopaminergic neuronal cells. However, the underlying mechanisms are still not fully understood. In this study, by using CATH.a cells, a dopaminergic neuronal cell line stably expressing angiotensin II type 1 receptor (AT1R) and angiotensin II type 2 receptor (AT2R), we tested the hypothesis that activation of autophagy contributed to the apoptosis triggered by Ang II. We showed that Ang II activated autophagy and triggered apoptosis in CATH.a cells in a dose-dependent manner. More importantly, inhibition of autophagy by 3-methyladenine markedly attenuated the apoptosis caused by Ang II in CATH.a cells. In addition, the Ang II-induced autophagy and subsequent cell apoptosis could be fully abolished by an AT1R antagonist losartan rather than PD1223319, an antagonist for AT2R. Taken together, our study provides the first evidence that Ang II triggers apoptosis via activation of autophagy in a dopaminergic neuronal cell line through an AT1R-mediated manner. These findings have deepened our understanding on the role of Ang II in the pathogenesis of PD and support the use of AT1R antagonists for the treatment of this devastating neurodegenerative disease.
我们最近的研究表明，肾素-血管紧张素系统的主要成分血管紧张素II（Ang II）通过引发多巴胺能神经元细胞凋亡参与帕金森病（PD）的发病机制。然而，其潜在机制仍未完全阐明。在本研究中，我们使用稳定表达血管紧张素II 1型受体（AT1R）和血管紧张素II 2型受体（AT2R）的多巴胺能神经元细胞系CATH.a细胞，验证了自噬激活导致Ang II触发细胞凋亡这一假说。我们发现，Ang II以剂量依赖的方式激活CATH.a细胞中的自噬并引发细胞凋亡。更重要的是，3-甲基腺嘌呤抑制自噬可显著减轻Ang II在CATH.a细胞中引起的细胞凋亡。此外，AT1R拮抗剂氯沙坦可完全消除Ang II诱导的自噬及随后的细胞凋亡，而AT2R拮抗剂PD1223319则不能。综上所述，我们的研究首次证明，Ang II通过AT1R介导的方式激活多巴胺能神经元细胞系中的自噬从而触发细胞凋亡。这些发现加深了我们对Ang II在PD发病机制中作用的理解，并支持使用AT1R拮抗剂治疗这种毁灭性神经退行性疾病。
