Central actions of angiotensin II in the control of fluid balance

描述（由申请人提供）：肾素-血管紧张素系统（RAS）是密集研究的焦点，因为它与心血管疾病的发展密切相关。RAS的活性成分，肽激素血管紧张素II（AngII），是心血管和体液稳态的重要调节剂。因此，积极研究响应于AngII的受体和由AngII结合引发的细胞、基因组和生理作用，以努力理解心血管疾病（如高血压、动脉粥样硬化和心力衰竭）发展的基础。体液稳态与心血管功能密切相关，取决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的稳定性的主要行为是水和盐的摄入。AngII在这些动机行为的控制中起着重要作用。肾上腺类固醇还进一步调节大脑对AngII的反应，从而调节口渴和盐的食欲。由于所有动物体内钠平衡的调节是体液稳态的一个关键方面，因此控制钠摄入量是治疗高血压的一个重要重点。虽然所有高血压患者都被建议限制钠的摄入量，但许多人很难遵守。因此，对这种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影响。1型（AT 1）AngII受体亚型主要负责对该肽的生理和行为反应。对于AT 1受体，有大量关于G蛋白活化介导的细胞信号传导的文献。然而，AT 1受体现在也被认为与激活非传统信号通路有关，包括丝裂原活化蛋白激酶（MAPK）的激活。最近，我们已经证明，血管紧张素II诱导的盐食欲是由MAPK激活，而不是更传统的G蛋白介导的信号与AT 1受体。在本申请中，我们提出通过使用各种药物条件来分离AT 1受体信号传导的不同分支来研究有助于盐食欲的细胞和神经解剖学机制：（1）AngII，其激活所有信号传导途径;（2）肽Sar 1、Ile 4、Ile 8-AngII，其仅激活MAPK;和（3）AngII与MEK抑制剂组合，其仅激活传统的G蛋白介导的信号传导。使用这些药物组合，我们将解决：（1）连接AT 1受体与MAPK信号传导的细胞中介蛋白，（2）AT 1-R介导的MAPK激活在诱导盐食欲的生理状态下的作用，（3）在盐食欲发展中使用的神经回路，以及（4）允许肾上腺类固醇调节盐食欲的细胞机制。激素血管紧张素II是密集研究的焦点，因为它与心血管疾病的发展密切相关。在这种激素在体内的许多作用中，血管紧张素II是通过协调生理作用（如肾脏和心血管功能）与饮水和盐（钠）摄入行为来调节体液平衡的重要调节剂。由于所有动物的钠平衡调节是体液调节的一个关键方面，因此控制钠摄入量是治疗高血压的一个重要重点。虽然所有高血压患者都被建议限制钠的摄入量，但许多人很难遵守。因此，对这种行为的理解对于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.