Differential effect of angiotensin II and blood pressure on hippocampal inflammation in mice
Differential effect of angiotensin II and blood pressure on hippocampal inflammation in mice
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DOI：
10.1186/s12974-018-1090-z
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发表时间：
2018-02-28
影响因子：
9.3
通讯作者：
Girouard, Helene
中科院分区：
文献类型：
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作者：
Iulita, M. Florencia;Vallerand, Diane;Girouard, Helene
背景：血管紧张素 II (Ang II) 是一种参与高血压发展的肽激素，会引起全身和大脑炎症，影响对血压控制很重要的大脑区域。高血压与炎症之间是双向的因果关系，但血压在诱发脑炎症中的作用尚不清楚。特定大脑区域的脆弱性，特别是那些对记忆很重要的区域，也令人感兴趣。方法：我们使用分子生物学方法、免疫组织化学和电子显微镜来检查血管紧张素II的高血压和促炎作用之间的相互依赖性。我们通过给予抑制性（200 ng/kg/min）或抑制性 Ang II 剂量（1000 或 1900 ng/kg/min）联合或不联合肼苯哒嗪 (150 mg/L) 1 周来检查血压的影响，并使用去氧肾上腺素独立于肾素-血管紧张素系统来升高血压。 结果：Ang II 增加了离子钙结合适配器分子 1 (Iba-1) 全脑和海马中的水平（小胶质细胞增生的标志物）呈剂量依赖性。加压的 Ang II 诱导小胶质细胞形态的特定变化，表明功能表型的差异。在接受抑制性 Ang II 的小鼠中观察到海马神经胶质纤维酸性蛋白 (GFAP) 增加，而在抑制性 Ang II 输注 7 天后没有观察到脑神经胶质增生的诱导。尽管去氧肾上腺素导致星形胶质细胞增多，但它并不影响 Iba-1 的表达。加压 Ang II 会刺激海马体中 TNF-α 的产生，而每日使用肼苯哒嗪治疗可阻止这种增加。肼屈嗪还降低了 GFAP 和 Iba-1 水平。随着灌注时间延长（14 天），抑制 Ang II 会导致一些但不是全部的抑制剂量下检测到的炎症变化，主要是 CD68 和 Iba-1 增加，但 GFAP 或 TNF-α 不增加。结论：血压和 Ang II 对小鼠海马炎症的影响不同。控制血压和血管紧张素II水平可以预防或减少脑部炎症，从而预防或减少与高血压相关的脑功能障碍。
Background: Angiotensin II (Ang II), a peptide hormone involved in the development of hypertension, causes systemic and cerebral inflammation, affecting brain regions important for blood pressure control. The cause-and-effect relationship between hypertension and inflammation is two-way, but the role of blood pressure in the induction of cerebral inflammation is less clear. The vulnerability of specific brain regions, particularly those important for memory, is also of interest.Methods: We used molecular biology approaches, immunohistochemistry, and electron microscopy to examine the interdependence between the hypertensive and pro-inflammatory effects of Ang II. We examined the effect of blood pressure by administering a subpressive (200 ng/kg/min) or a pressive Ang II dose (1000 or 1900 ng/kg/min) with and without hydralazine (150 mg/L) for 1 week and used phenylephrine to increase blood pressure independently of the renin-angiotensin system.Results: Ang II increased ionized calcium-binding adaptor molecule 1 (Iba-1) levels (marker of microgliosis) in the whole brain and in the hippocampus in a dose-dependent manner. Pressive Ang II induced specific changes in microglial morphology, indicating differences in functional phenotype. An increase in hippocampal glial fibrillary acidic protein (GFAP) was seen in mice receiving pressive Ang II, while no induction of cerebral gliosis was observed after 7 days of subpressive Ang II infusion. Although phenylephrine led to increased astrogliosis, it did not affect Iba-1 expression. Pressive Ang II stimulated TNF-alpha production in the hippocampus, and daily treatment with hydralazine prevented this increase. Hydralazine also reduced GFAP and Iba-1 levels. With longer perfusion (14 days), subpressive Ang II led to some but not all the inflammatory changes detected with the pressive doses, mainly an increase in CD68 and Iba-1 but not of GFAP or TNF-alpha.Conclusions: Blood pressure and Ang II differentially contribute to hippocampal inflammation in mice. Control of blood pressure and Ang II levels should prevent or reduce brain inflammation and therefore brain dysfunctions associated with hypertension.