ANG II AND AVP ISORECEPTORS IN BLOOD PRESSURE

血管加压素（AVP）和血管紧张素II（AngII）激素系统调节 影响多个器官系统的各种生理功能。 最重要的是它们在血压调节中的作用。 我们 长期目标是剖析小说的特殊贡献 血管紧张素Ⅱ和精氨酸加压素受体在正常人血压调节中的作用 病理生理状态。AngII和AVP的几种同种受体 最近被鉴定了。 其中，双AngII/AVP 受体，我们分离，阐明了新的信息，提供了 新的假设和问题的基础。 在这项研究中，我们 将测试以下假设：1）基于检测到的丰度 通过免疫细胞化学定位AngII/AVP 肾外髓上皮细胞受体多肽 粗的升肢小管和内髓集合管，我们 假设AngII/AVP受体是一种重要的肾脏生理性 血管紧张素II和AVP的靶向，因此在盐- 水平衡和血压调节; 2）在阐明 Dahl盐敏感大鼠的功能性显著突变 AngII/AVP受体，我们假设AngII/AVP受体是一种 Dahl盐敏感性高血压的遗传决定因素 敏感性高血压大鼠。 因此，以下具体目标 优先考虑：I）潜在病理生理受累的解剖 血管紧张素Ⅱ/精氨酸加压素受体在高血压中的作用 N119 S和C163 R取代对细胞凋亡的特异性贡献 对Ang II和AVP的敏感性增加， 在Dahl S AngII/AVP受体中观察到; 1B）遗传共分离 血管紧张素Ⅱ/精氨酸加压素受体与血压及肾功能的关系 F2（Dahl S雄性x Dahl R雌性）队列中的病理学， 雄性和雌性大鼠，以确定是否突变AngII/AVP 受体与高血压和/或高血压共分离 肾脏疾病II）AngII/AVP的生理作用的剖析 受体：2A）组织特异性、空间和时间表达模式 在AngII/AVP受体基因的开发中， 用于评估其在综合生物实验系统中的功能 如在下面提出的基因靶向实验中。2.针对性 破坏小鼠中的AngII/AVP受体基因，以确定其 在综合生物实验系统中的生理作用。 这些 研究将阐明AngII/AVP受体的生理作用 并将AngII/AVP受体的状态定义为候选者 高血压易感基因，从而为直接 评估这种受体在盐敏感性细胞中的机制作用 高血压及其在高血压发展中的作用 选择性的人群。

Vasopressin (AVP) and angiotensin II (AngII) hormonal systems modulate a variety of physiologic functions affecting multiple organ systems. Of singular importance, is their role in blood pressure regulation. Our long term objective is to dissect the specific contribution of novel AngII and AVP receptors in blood pressure regulation in normal and pathophysiological states. Several isoreceptors for both AngII and AVP have been recently characterized. Of these, the dual AngII/AVP receptor, isolated by us, elucidates novel information providing the bases for new hypotheses and questions. In this research proposal, we will test the following hypotheses: 1) Based on the detected abundance and assignment by immunocytochemical localization of the AngII/AVP receptor polypeptide to renal epithelial cells of the outer medullary thick ascending limb tubules and inner medullary collecting ducts, we hypothesize that the AngII/AVP receptor is a prominent renal physiologic target for AngII and AVP, and therefore plays an important role in salt- water balance and blood pressure regulation; 2) Based on the elucidation of functional significant mutations in the Dahl Salt-Sensitive rat AngII/AVP receptor, we hypothesize that the AngII/AVP receptor is a genetic determinant for salt-sensitive hypertension in the Dahl Salt- Sensitive hypertensive rat. Accordingly, the following specific aims are prioritized: I) Dissection of potential pathophysiologic involvement of the AngII/AVP receptor in hypertension 1A) Assessment of the specific contribution(s) of N119S and C163R substitutions to the increased sensitivity to Ang II and AVP and enhanced Gs-coupling observed in the Dahl S AngII/AVP receptor; 1B) Genetic cosegregation analysis of the AngII/AVP receptor with blood pressure and renal pathology in an F2 (Dahl S male x Dahl R female) cohort comprised of male and female rats in order to determine whether the mutant AngII/AVP receptor cosegregates with high blood pressure and/or with hypertensive renal disease. II) Dissection of physiologic role of the AngII/AVP receptor: 2A) Tissue specific, spatial and temporal expression patterns in development of the AngII/AVP receptor gene, establishing a foundation for assessing its function in an integrated biologic experimental system as in the gene targeting experiments proposed below. 2B) Targeted disruption of the AngII/AVP receptor gene in mice in order to define its physiologic role in an integrated biologic experimental system. These studies will elucidate the physiologic role of the AngII/AVP receptor and will define the status of the AngII/AVP receptor as a candidate hypertension susceptibility gene, thus paving the way for the direct assessment of the mechanistic role of this receptor in salt-sensitive hypertension and its role in the development of hypertension in selective human populations.