From the Department of Pharmacology and Experimental Therapeutics (J.X., S.M., E.L.), Louisiana State University Health Sciences Center, New Orleans.
Cardiovascular Center of Excellence (J.X., S.M., E.L.), Louisiana State University Health Sciences Center, New Orleans.
Hypertension. 2019 Jun;73(6):1266-1274. doi: 10.1161/HYPERTENSIONAHA.119.12832.
Chronic activation of the brain renin-angiotensin system contributes to the development of hypertension by altering autonomic balance. Beyond the essential role of Ang II (angiotensin II) type 1 receptors, ADAM17 (A disintegrin and metalloprotease 17) is also found to promote brain renin-angiotensin system overactivation. ADAM17 is robustly expressed in various cell types within the central nervous system. The aim of this study was to determine whether ADAM17 modulates presympathetic neuronal activity to promote autonomic dysregulation in salt-sensitive hypertension. To test our hypothesis, ADAM17 was selectively knocked down in glutamatergic neurons using Cre-loxP technology. In mice lacking ADAM17 in glutamatergic neurons, the blood pressure increase induced by deoxycorticosterone acetate-salt treatment was blunted. Deoxycorticosterone acetate-salt significantly elevated cardiac and vascular sympathetic drive in control mice, while such effects were reduced in mice with ADAM17 knockdown. This blunted sympathoexcitation was extended to the spleen, with a lesser activation of the peripheral immune system, translating into a sequestration of circulating T cells within this organ, compared with controls. Within the paraventricular nucleus, Ang II-induced activation of kidney-related presympathetic glutamatergic neurons was reduced in ADAM17 knockdown mice, with the majority of cells no longer responding to Ang II stimulation, confirming the supportive role of ADAM17 in increasing presympathetic neuronal activity. Overall, our data highlight the pivotal role of neuronal ADAM17 in regulating sympathetic activity and demonstrate that activation of ADAM17 in glutamatergic neurons leads to a selective increase of sympathetic output, but not vagal tone, to specific organs, ultimately contributing to dysautonomia and salt-sensitive hypertension.
脑肾素-血管紧张素系统的慢性激活通过改变自主平衡促进高血压的发展。除了血管紧张素 II（Ang II）1 型受体的基本作用外，ADAM17（解整合素和金属蛋白酶 17）也被发现可促进脑肾素-血管紧张素系统过度激活。ADAM17 在中枢神经系统的各种细胞类型中均有强烈表达。本研究旨在确定 ADAM17 是否调节节前交感神经元活性以促进盐敏感高血压中的自主神经失调。为了验证我们的假设，我们使用 Cre-loxP 技术选择性敲低谷氨酸能神经元中的 ADAM17。在缺乏谷氨酸能神经元 ADAM17 的小鼠中，地塞米松醋酸盐-盐处理引起的血压升高减弱。地塞米松醋酸盐显著增加了对照组小鼠的心脏和血管交感神经驱动，而 ADAM17 敲低的小鼠则减少了这种作用。这种交感神经兴奋的减弱扩展到脾脏，外周免疫系统的激活程度降低，与对照组相比，循环 T 细胞在该器官内被隔离。在室旁核中，ADAM17 敲低的小鼠中，Ang II 诱导的肾脏相关节前谷氨酸能神经元的激活减少，大多数细胞不再对 Ang II 刺激产生反应，证实了 ADAM17 在增加节前神经元活性中的支持作用。总的来说，我们的数据强调了神经元 ADAM17 在调节交感神经活动中的关键作用，并表明谷氨酸能神经元中 ADAM17 的激活导致特定器官的交感输出选择性增加，但迷走神经张力不变，最终导致自主神经失调和盐敏感高血压。
