Central actions of angiotensin II in the control of fluid balance

描述(申请人提供)：肾素-血管紧张素系统(RAS)是一个紧张研究的焦点，因为它与心血管疾病的发展密切相关。血管紧张素II(AngII)是RAS的活性成分，是心血管和体液平衡的重要调节因子。因此，为了了解高血压、动脉粥样硬化和心力衰竭等心血管疾病的发生基础，对血管紧张素Ⅱ受体以及血管紧张素Ⅱ结合所启动的细胞、基因组和生理活动进行了积极的研究。体液动态平衡与心血管功能有着千丝万缕的联系，它依赖于互补的生理和行为机制的协调调节。确保流体基质的体积和组成稳定的主要行为是水和盐的摄入量。Angii重要地参与了对这些动机行为的控制。肾上腺类固醇还进一步调节大脑对血管紧张素转换酶的反应，从而调节口渴和食盐量。由于所有动物体内钠平衡的调节是体液平衡的一个关键方面，因此控制钠的摄入量是高血压治疗的一个重要重点。虽然所有高血压患者都得到了限制钠摄入量的建议，但许多人在遵守方面存在很大困难。因此，对这一行为的理解对于高血压和心血管疾病的病理生理学具有重要的意义。1型(AT1)血管紧张素Ⅱ受体亚型主要负责对这种多肽的生理和行为反应。对于AT1受体，有相当多的文献关于G蛋白激活介导的细胞信号转导。然而，AT1受体也被认为与激活非传统信号通路有关，包括丝裂原激活蛋白激酶(MAPK)的激活。最近，我们已经证明，Angii诱导的食盐反应是由MAPK激活启动的，而不是与AT1受体相关的更传统的G蛋白介导的信号转导。在目前的应用中，我们建议通过使用不同的药物条件来分离AT1受体信号的不同分支来研究抑制盐摄取的细胞和神经解剖学机制：(1)激活所有信号通路的AngII；(2)仅激活MAPK的多肽Sar1、Ile4、Ile8-AngII；以及(3)AngII与MEK抑制剂联合，仅激活传统的G蛋白介导的信号传递。使用这些药物组合，我们将解决：(1)连接AT1受体和MAPK信号的细胞中间蛋白，(2)AT1-R介导的MAPK在生理状态下诱导食盐食欲的作用，(3)用于食盐食欲发育的神经回路，以及(4)允许肾上腺类固醇调节食盐食欲的细胞机制。由于血管紧张素II与心血管疾病的发生密切相关，因此血管紧张素II一直是研究的热点。在体内这种荷尔蒙的许多作用中，血管紧张素II是一种重要的液体平衡调节器，它通过协调生理活动，如肾脏和心血管功能，以及饮水和摄取盐(钠)的行为。由于所有动物体内钠平衡的调节是体液调节的一个关键方面，因此控制钠的摄入量是高血压治疗的重要重点。虽然所有高血压患者都得到了限制钠摄入量的建议，但许多人在遵守方面存在很大困难。因此，对这一行为的理解对高血压和心血管疾病的发展具有重要的影响。

DESCRIPTION (provided by applicant): The renin-angiotensin system (RAS) is a focus of intense research because it has been strongly implicated in the development of cardiovascular disease. The active component of the RAS, the peptide hormone angiotensin II (AngII), is an important regulator of cardiovascular and body fluid homeostasis. Therefore, the receptors that respond to AngII and the cellular, genomic, and physiological actions initiated by AngII binding are actively studied in an effort to understand the foundation for the development of cardiovascular diseases, such as hypertension, atherosclerosis, and cardiac failure. Body fluid homeostasis, which is intricately connected with cardiovascular function, depends on the coordinated regulation of complementary physiological and behavioral mechanisms. The principle behaviors that ensure stability of volume and composition of the fluid matrix are water and salt intake. AngII is importantly involved in the control of these motivated behaviors. Adrenal steroids also further regulate the brain's responsivity to AngII, thereby modulating thirst and salt appetite. Because the regulation of sodium balance in all animals is a key aspect of body fluid homeostasis, control of sodium intake is an important point of emphasis in the treatment of hypertension. While all hypertensive patients are counseled to restrict their sodium intake, many have great difficulty in complying. Thus, an understanding of this behavior has important ramifications with respect to pathophysiology of hypertension and cardiovascular disease. The Type 1 (AT1) AngII receptor subtype is primarily responsible for the physiological and behavioral responses to this peptide. For the AT1 receptor, there is considerable literature on cell signaling mediated by G-protein activation. However, AT1 receptors are now also recognized to be linked to activation nontraditional signaling pathways, including activation of mitogen activated protein kinases (MAPK). Recently, we have demonstrated that AngII-induced salt appetite is initiated by MAPK activation and not the more traditional G- protein mediated signaling associated with AT1 receptors. In the present application, we propose to investigate the cellular and neuroanatomical mechanisms that subserve salt appetite by using various drug conditions to isolate different branches of AT1 receptor signaling: (1) AngII, which activates all signaling pathways; (2) the peptide Sar1,Ile4,Ile8-AngII, which activates only MAPK; and (3) AngII combined with a MEK inhibitor, which activates only the traditional G-protein mediated signaling. Using these drug combinations, we will address: (1) the cellular intermediary proteins that connect the AT1 receptor to MAPK signaling, (2) the role of AT1-R mediated MAPK activation under physiological states that induce salt appetite, (3) the neurocircuitry that is employed in the development of salt appetite, and (4) the cellular mechanisms that permit adrenal steroids to modulate salt appetite. The hormone angiotensin II is a focus of intense research because it has been strongly implicated in the development of cardiovascular disease. Of the many actions of this hormone within the body, angiotensin II is an important regulator of fluid balance by coordinating physiological actions, such as kidney and cardiovascular function, with the behaviors of water drinking and the ingestion of salt (sodium). Because the regulation of sodium balance in all animals is a key aspect of body fluid regulation, control of sodium intake is an important point of emphasis in the treatment of hypertension. While all hypertensive patients are counseled to restrict their sodium intake, many have great difficulty in complying. Thus, an understanding of this behavior has important ramifications with respect to the development of hypertension and cardiovascular disease.