血管紧张素Ⅱ对鱼藤酮诱导的多巴胺能细胞氧化应激的影响
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国家自然科学基金(81271418);江苏省自然科学基金(BK2012524);江苏省“六大人才高峰”项目(N02012-WS-086)


Effects of angiotensin Ⅱ on oxidative stress in rotenone-induced dopaminergic cells
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    摘要:

    目的:探讨血管紧张素Ⅱ(angiotensin Ⅱ,AngⅡ)对多巴胺能细胞损伤的影响及其机制。方法:体外培养CATH.a细胞,鱼藤酮和(或)Ang Ⅱ处理细胞24 h。采用噻唑蓝(methylthiazolyldiphenyl-tetrazolium bromide,MTT)法检测细胞存活率,蛋白印迹技术检测血管紧张素Ⅱ-1型受体(angiotensin Ⅱ type 1 receptor,AT1R)和血管紧张素Ⅱ-2型受体(angiotensin Ⅱ type 2 receptor,AT2R)蛋白表达,流式细胞仪检测细胞内活性氧(reactive oxygen species,ROS)含量,荧光定量PCR检测尼克酰胺腺嘌呤二核苷酸磷酸(nicotinamide adenine dinucleotide phosphate,NADPH)氧化酶亚基gp91phox和p67phox基因表达,免疫荧光检测gp91phox蛋白表达。结果:Ang Ⅱ通过AT1R导致鱼藤酮诱导的CATH.a细胞存活率降低(P < 0.05)。Ang Ⅱ使NADPH氧化酶亚基gp91phox和p67phox表达增加(P < 0.05),并呈剂量依赖性促进细胞内ROS产生。AT1R阻滞剂氯沙坦和NADPH氧化酶抑制剂夹竹桃麻素使Ang Ⅱ诱导的ROS产生减少(P < 0.01)。结论:Ang Ⅱ作用于AT1R,通过NADPH氧化酶产生ROS,促进鱼藤酮诱导的多巴胺能细胞损伤,参与帕金森病的发生与发展。

    Abstract:

    Objective:To investigate the effects of angiotensin Ⅱ (Ang Ⅱ) on injury of dopaminergic cells and its underlying mechanisms. Methods: CATH.a cells, a dopaminergic neuronal cell line stably expressing Ang Ⅱtype 1 receptor (AT1R) and Ang Ⅱ type 2 receptor (AT2R), were exposed to rotenone alone or in combination with Ang Ⅱ for 24 h. The cell survival rate was measured by methyl thiazolyl diphenyl-tetrazolium bromide (MTT). The protein levels of AT1R and AT2R were detected by Western blot. The intracellular levels of reactive oxygen species (ROS) were monitored using flow cytometry. The levels of gp91phox and p67phox, the two main subunits of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, were examined by RT-PCR and immunofluorescence stainning. Results: The results showed that rotenone caused a significantly reduction on the survival rate of CATH.a cells (P < 0.05), which could be further exacerbated by Ang Ⅱ via an AT1R-dependent manner (P < 0.05). Meanwhile, we revealed that Ang Ⅱ exacerbated the rotenone-induced increase in intracellular levels of ROS (P < 0.05) as well as the expression of gp91phox and p67phox (P < 0.05). This exacerbation was abolished by NADPH oxidase inhibitor apocynin (P < 0.01) or AT1R blocker losartan (P < 0.01). Conclusion:These findings indicate that Ang Ⅱ interacts with AT1R and subsequently exacerbates the rotenone-induced injury of dopaminergic cells via elevation of ROS levels through a NADPH oxidase-dependent manner. These findings have deepened our understanding on the role of Ang Ⅱ in the pathogenesis of Parkinson’s disease, and support the use of AT1R blockers in the treatment of this devastating disease.

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赵洪锐,吴 亮,田有勇,高 擎,曹 洁,欧 洲,沙志涛,耿 丛,张颖冬.血管紧张素Ⅱ对鱼藤酮诱导的多巴胺能细胞氧化应激的影响[J].南京医科大学学报(自然科学版),2015,(6):766-771

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  • 收稿日期:2014-12-25
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  • 在线发布日期: 2015-06-08
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