室旁核ROS/MAPK/AT1-R通路在盐敏感性高血压中的作用及其机制

The sympathoexcitation plays a vital role in the pathogenesis and development of hypertension. Presympathetic neurons are distributed in the hypothalamic paraventricular nucleus (PVN). Our preliminary studies discovered angiotensin II (Ang II) type 1 receptor (AT1-R) in the PVN may be involved in sympathoexcitation and salt-sensitive hypertension, which needs to be further clarified. This study will be conducted with electrophysiological, molecular biological and morphological methods, and adopt high salt-induced hypertensive rats and neuronal cells to study the effect and its mechanism of AT1-R upregulation within the PVN. Also, we will further investigate whether AT1-R is upregulated via the NAD(P)H oxidase/ROS/MAPK/AP-1 pathway, by using specific inhibitors, gene overexpression and RNA interference techiques. This study will significantly improve our understanding of AT1-R within the PVN in sympathoexcitation and vascular remodeling during salt-sensitive hypertension, and likely provide a potential novel therapeutic target for prevention and treatment of salt-sensitive hypertension.

交感神经活动过度激活是高血压发生发展的重要机制。我们前期研究发现盐敏感性高血压大鼠室旁核神经元中血管紧张素II受体1型(AT1-R)上调引起外周交感神经活动增强，但室旁核神经元AT1-R上调的机制尚不明确。本项目将以高盐诱导的Dahl盐敏感性高血压大鼠模型和室旁核离体神经元为对象，采用电生理、分子生物学和形态学等方法，首先观察高盐诱导高血压的发病过程中室旁核中血管紧张素II生成和AT1-R表达变化情况及其与外周交感神经活动、血管重构和血压之间的关系；继而应用ROS/MAPK/AT1-R通路关键酶的抑制剂、基因过表达或干扰RNA，从整体和细胞水平阐明室旁核神经元中AT1-R上调是否受NAD(P)H氧化酶/ROS/MAPK/AP-1通路调控。本项目将揭示盐敏感性高血压发生发展过程中室旁核神经元AT1-R上调进而影响外周交感神经活动、血管重构和血压的机制，有望为高血压的防治提供新的药物作用靶点。

交感神经活动过度激活是高血压发生发展的重要机制。我们前期研究发现盐敏感性高血压大鼠室旁核神经元中血管紧张素II受体1型(AT1-R)上调引起交感神经活动增强，但室旁核AT1-R上调的机制尚不明确。本项目以高盐诱导的Dahl盐敏感性高血压大鼠模型为对象，采用电生理、分子生物学和形态学等方法，观察高盐诱导高血压的发病过程中室旁核中AT1-R表达情况及其与交感神经活动、血管重构和血压之间的关系；应用ROS/MAPK/AT1-R通路关键酶的抑制剂，阐明了室旁核AT1-R上调可能是受NAD(P)H氧化酶/ROS/MAPK通路调控。本项目主要取得以下研究结果：(1)发现高盐饮食可引起Dahl盐敏感性大鼠PVN中ROS产生增加、MAPK激活和AT1-R上调，肾交感神经活动增强，血管重构，血压升高。(2)发现PVN中AT1-R的上调可作为盐敏感性高血压的发病机制，阻断PVN中AT1-R可降低PVN中ROS的产生，抑制MAPK的激活，降低交感神经活动，抑制血管重构，进而改善盐敏感性高血压。(3)发现PVN中ROS产生增加可作为盐敏感性高血压的发病机制，抑制PVN中ROS的产生可降低PVN中ROS的产生，抑制MAPK的激活，下调AT1-R，降低交感神经活动，抑制血管重构，进而改善盐敏感性高血压。(4)发现PVN中MAPK的上调可作为盐敏感性高血压的发病机制，抑制PVN中的MAPK激活可降低PVN中ROS的产生，抑制MAPK的激活，下调AT1-R，可降低交感神经活动，抑制血管重构，进而改善盐敏感性高血压。结论：本项目研究发现高盐诱导盐敏感性高血压时，下丘脑室旁核AT1-R被激活，通过NAD(P)H氧化酶/ROS/MAPK信号通路进一步使室旁核AT1-R上调，引起交感神经活动增强、血管重构和血压升高，从而加重高血压。本项目揭示了盐敏感性高血压发生发展过程中室旁核AT1-R上调进而影响交感神经活动、血管重构和血压的机制，有望为高血压的防治提供新的药物作用靶点。