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一系列的生理和行为机制，这些机制可以监测、响应和缓解体液稳态的扰动。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，特别是在对低血容量的反应中。血管紧张素转换酶影响多个系统，包括肾脏、肾上腺、胃肠道、血管平滑肌和大脑。血管紧张素转换酶的中枢作用包括增加水和氯化钠的摄入量、维持体液和心血管内环境平衡的关键行为。这些行为效应主要是通过血管紧张素转换酶1型(AT1)受体介导的，AT1受体刺激多种细胞内信号通路，包括导致三磷酸肌醇(IP3)形成和蛋白激酶C(PKC)激活的增加，以及增加丝裂原活化蛋白(MAP)激酶的磷酸化。最近的实验表明，这些途径对血管紧张素转换酶诱导的水和氯化钠摄入量的相对贡献不同。本方案中的实验使用行为、药理学、电生理、分子和神经解剖学方法来探索这些细胞内信号通路在控制血管紧张素转换酶诱导的水分和氯化钠中的作用。具体地说，这些实验将(1)确定GQ/IP3/PKC和MAP激酶信号通路在AngII诱导的水和盐摄入中的作用；(2)确定单个信号通路对脑内AngII作用的主要和下游部位神经活动的作用；以及(3)测试这些信号通路和受体磷酸化在多种AngII处理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学、解剖学、电生理学和神经化学的角度回答这些问题。

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.