Role of angiotensin II receptor signaling pathways in body fluid homeostasis

描述（由申请人提供）：维持心血管健康依赖于许多生理和行为机制，这些机制可以监测、响应和减轻体液稳态的扰动。血管紧张素II （AngII）是肾素-血管紧张素系统的生物活性产物，是这些作用的重要组成部分，特别是对低血容量的反应。AngII影响许多系统，包括肾脏、肾上腺、胃肠道、血管平滑肌和大脑。AngII的主要作用包括增加水和盐的摄入量，维持体液和心血管稳态的关键行为。这些行为效应主要是通过AngII型1 （AT1）受体介导的，该受体刺激几种细胞内信号通路，包括导致肌醇三磷酸（IP3）形成和蛋白激酶C （PKC）激活增加的信号通路，以及增加丝裂原活化蛋白（MAP）激酶磷酸化的信号通路。最近的实验表明，这些途径对AngII诱导的水和NaCl摄入量的相对贡献不同。本实验采用行为学、药理学、电生理、分子和神经解剖学的方法来探索这些细胞内信号通路在控制AngII诱导的水和NaCl中的作用。具体而言，实验将(1)确定Gq/IP3/PKC和MAP激酶信号通路在血管诱导的水和NaCl摄入中的作用；(2)确定各个信号通路对大脑AngII作用的初级和下游部位的神经活动的作用；(3)测试这些信号通路和受体磷酸化在多次AngII治疗后细胞内和行为反应脱敏中的作用。这些实验使用多方面的方法和各种技术从行为、解剖、电生理和神经化学的角度来回答这些问题。公共卫生相关性：水、盐和食物的摄入对许多身体系统的正常功能至关重要。与能量和体液失衡相关的疾病包括高血压、肥胖、心脏病和糖尿病。了解激素调节水、盐和食物摄入的神经机制可能会导致新的治疗方法来对抗这些相关疾病状态。

DESCRIPTION (provided by applicant): Maintaining cardiovascular health relies on a number of physiological and behavioral mechanisms that monitor, respond to, and alleviate perturbations in body fluid homeostasis. Angiotensin II (AngII), the bioactive product of the renin-angiotensin system, is an important component of these actions, especially in the response to hypovolemia. AngII affects numerous systems including the kidney, adrenal gland, gastrointestinal tract, vascular smooth muscle, and brain. The central effects of AngII include increases in water and NaCl intake, critical behaviors for the maintenance of body fluid and cardiovascular homeostasis. These behavioral effects are mediated largely through AngII type 1 (AT1) receptors, which stimulate several intracellular signaling pathways including one that leads to increased inositol trisphosphate (IP3) formation and protein kinase C (PKC) activation, and another that increases phosphorylation of mitogen activated protein (MAP) kinase. Recent experiments suggest different relative contributions of these pathways to the water and NaCl intake induced by AngII. The experiments in the present proposal use behavioral, pharmacological, electrophysiological, molecular, and neuroanatomical approaches to explore the role of these intracellular signaling pathways in the control of AngII- induced water and NaCl. Specifically, the experiments will (1) determine the roles of the Gq/IP3/PKC and MAP kinase signaling pathways in AngII-induced water and NaCl intake; (2) determine the role of individual signaling pathways on neural activity at primary and downstream sites of AngII action in the brain; and (3) test the role of these signaling pathways and receptor phosphorylation on desensitization of the intracellular and behavioral responses after multiple treatments with AngII. These experiments use a multifaceted approach and a variety of techniques to answer these questions from behavioral, anatomical, electrophysiological, and neurochemical perspectives. PUBLIC HEALTH RELEVANCE: Ingestion of water, salt, and food is critical for proper function of numerous body systems. Disorders related to energy and fluid imbalance include hypertension, obesity, heart disease, and diabetes. Understanding the neural mechanisms through which hormones mediate the ingestion of water, salt, and food may lead to novel therapeutic approaches to combat these relevant disease states.