Angiotensin type 2 receptors: role in aging and neuroinflammation in the substantia nigra,Brain, Behavior, and Immunity

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Angiotensin type 2 receptors: role in aging and neuroinflammation in the substantia nigra
Brain, Behavior, and Immunity ( IF 8.8 ) Pub Date : 2020-07-01 , DOI: 10.1016/j.bbi.2019.12.011
Ana I Rodriguez-Perez ₁ , Pablo Garrido-Gil ₁ , Maria A Pedrosa ₁ , Maria Garcia-Garrote ₁ , Rita Valenzuela ₁ , Gemma Navarro ₂ , Rafael Franco ₂ , Jose L Labandeira-Garcia ₁

Affiliation

Overactivity of the angiotensin-type-1 receptor (AT1)/NADPH-oxidase axis enhances aging processes, neuroinflammation and neurodegeneration. The role of AT2 receptors in the above-mentioned AT1-related effects in the aged brain, particularly substantia nigra, was investigated in this study. In the nigra, we observed a progressive decrease in AT2 mRNA expression with aging, and AT2 deletion led to changes in spontaneous motor behavior, dopamine receptors, renin-angiotensin system, and pro-oxidative and pro-inflammatory markers similar to those observed in aged wild type (WT) mice. Both aged WT mice and young AT2 KO mice showed an increased AT1, decreased MAS receptor and increased angiotensinogen mRNA and/or protein expression, as well as upregulation of pro- oxidative and pro-inflammatory markers. In cultures of microglial cells, activation of AT2 receptors inhibited the LPS-induced increase in AT1 mRNA and protein expression and neuroinflammatory markers. Both in AT2 KO microglial cultures and microglia obtained from adult AT2 KO mice, an increase in AT1 mRNA expression was observed. In cultured dopaminergic neurons, AT2 activation down-regulated AT1 mRNA and protein, and dopaminergic neurons from adult AT2 KO mice showed upregulation of AT1 mRNA expression. Both in microglia and dopaminergic neurons the pathway AT2/nitric oxide/cyclic guanosine monophosphate mediates the regulation of the AT1 mRNA and protein expression through downregulation of the Sp1 transcription factor. Mas receptors are also involved in the regulation of AT1 mRNA and protein expression by AT2. The results suggest that an aging-related decrease in AT2 expression plays a major role in the aging-related AT1 overexpression and AT1-related pro-inflammatory pro-oxidative effects.

中文翻译：

血管紧张素 2 型受体：在黑质衰老和神经炎症中的作用

血管紧张素 1 型受体 (AT1)/NADPH-氧化酶轴的过度活性会增强衰老过程、神经炎症和神经退行性变。本研究研究了 AT2 受体在上述 AT1 相关效应中对老年大脑，特别是黑质的作用。在黑质中，我们观察到 AT2 mRNA 表达随着年龄的增长而逐渐降低，并且 AT2 缺失导致自发运动行为、多巴胺受体、肾素-血管紧张素系统以及促氧化和促炎标志物的变化，类似于在老年人中观察到的那些野生型（WT）小鼠。老年 WT 小鼠和年轻 AT2 KO 小鼠均表现出 AT1 增加、MAS 受体减少和血管紧张素原 mRNA 和/或蛋白质表达增加，以及促氧化和促炎标志物的上调。在小胶质细胞培养中，AT2 受体的激活抑制了 LPS 诱导的 AT1 mRNA 和蛋白质表达以及神经炎症标志物的增加。在 AT2 KO 小胶质细胞培养物和从成年 AT2 KO 小鼠获得的小胶质细胞中，观察到 AT1 mRNA 表达增加。在培养的多巴胺能神经元中，AT2 激活下调 AT1 mRNA 和蛋白质，成年 AT2 KO 小鼠的多巴胺能神经元显示 AT1 mRNA 表达上调。在小胶质细胞和多巴胺能神经元中，AT2/一氧化氮/环鸟苷一磷酸通路通过下调 Sp1 转录因子介导 AT1 mRNA 和蛋白质表达的调节。Mas 受体也参与 AT2 对 AT1 mRNA 和蛋白质表达的调节。

更新日期：2020-07-01

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