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Angiotensin II Triggers Apoptosis Via Enhancement of NADPH Oxidase-Dependent Oxidative Stress in a Dopaminergic Neuronal Cell Line

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Abstract

Numerous studies reveal that Angiotensin II (Ang II), the main effector of renin-angiotensin system, contributes to the pathogenesis of Parkinson’s disease (PD) via triggering dopaminergic cell loss. However, the underlying mechanisms remain largely unclear. In the current study, by using CATH.a cell, a dopaminergic neuronal cell line stably expressing Angiotensin II type 1 receptor (AT1R) and Angiotensin II type 2 receptor (AT2R), we showed that Ang II treatment triggered cell apoptosis in a dose-dependent manner, providing the first evidence that apoptotic cell death contributed to the dopaminergic cell loss induced by Ang II. Ang II treatment also led to a significant increment in intracellular reactive oxygen species generation, which could be fully abolished by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors apocynin or diphenylene iodonium, indicating that Ang II enhanced oxidative stress via a NADPH oxidase-dependent manner. More importantly, inhibition of oxidative stress by NADPH oxidase inhibitors partially attenuated cell apoptosis caused by Ang II, implying that the enhancement of NADPH oxidase-dependent oxidative stress contributed to the cell apoptosis triggered by Ang II. Furthermore, the Ang II-induced oxidative stress and subsequent apoptosis could be completely abolished by AT1R blocker losartan rather than AT2R blocker PD1223319, suggesting that the aforementioned detrimental effects of Ang II are mediated by AT1R. In summary, these findings have deepened our understanding on the role of Ang II in PD pathogenesis, and support the use of AT1R blockers in the treatment of this devastating disease.

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Acknowledgments

This work was supported by the grants from the Innovation Project for Postgraduates of Jiangsu Province to T.J. (CXLX13_561), the National Natural Science Foundation of China (81271418) and the Six Talent Summit of Jiangsu Province to Y.D.Z. (N02012-WS-086), and the Natural Science Foundation of Jiangsu Province to Y.Y.T. (BK2012524).

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Authors and Affiliations

  1. Department of Neurology, Nanjing First Hospital, Nanjing Medical University, No.68, Changle Road, Nanjing, 210006, People’s Republic of China

    Hong-Rui Zhao, Teng Jiang, You-Yong Tian, Qing Gao, Liang Wu & Ying-Dong Zhang

  2. Department of Neurology, Nanjing Brain Hospital, Nanjing Medical University, Nanjing, People’s Republic of China

    Zhang Li, Yang Pan & Jie Lu

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  1. Hong-Rui Zhao
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Correspondence to You-Yong Tian or Ying-Dong Zhang.

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Hong-Rui Zhao and Teng Jiang should be regarded as co-first authors.

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Zhao, HR., Jiang, T., Tian, YY. et al. Angiotensin II Triggers Apoptosis Via Enhancement of NADPH Oxidase-Dependent Oxidative Stress in a Dopaminergic Neuronal Cell Line. Neurochem Res 40, 854–863 (2015). https://doi.org/10.1007/s11064-015-1536-y

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