ANG II AND AVP ISORECEPTORS IN BLOOD PRESSURE

加压素(AVP)和血管紧张素II(AngII)激素系统的调节 影响多个器官系统的各种生理功能。 特别重要的是，它们在血压调节中的作用。我们的 长期目标是剖析小说的具体贡献 血管紧张素Ⅱ和血管紧张素转换酶受体在正常和正常血压调节中的作用 病理生理状态。血管紧张素转换酶Ⅱ和血管紧张素转换酶的几种同工受体 最近都被定性了。其中，双重AngII/AVP 受体，由我们分离，阐明新的信息提供 新假设和新问题的基础。在这项研究提案中，我们 将检验以下假设：1)基于检测到的丰度 AngiI/AVP的免疫细胞化学定位 肾外髓质上皮细胞的受体多肽 粗大的升肢小管和内髓集合管 假设AngII/AVP受体是一种显著的肾脏生理学机制 作为Angii和AVP的靶标，因此在SALT- 水平衡与血压调节；2)在阐明的基础上 Dahl盐敏感大鼠功能显著突变的研究 AngiI/AVP受体，我们假设AngII/AVP受体是一个 达尔盐区盐敏感型高血压的遗传决定因素 敏感的高血压大鼠。因此，有以下具体目标 优先考虑：i)解剖潜在的病理生理损害 血管紧张素Ⅱ/血管加压素受体在高血压中的作用 N119S和C163R替换对基因的具体贡献(S) 增强对Ang II和AVP的敏感性和增强Gs偶联 DAHL-S血管紧张素Ⅱ/血管加压素受体观察；1B)遗传共分离 血管紧张素Ⅱ/精氨酸加压素受体与血压和肾脏的关系 F2(S男性x R女性)队列中的病理学 雄性和雌性大鼠，以确定突变的AngiI/AVP是否 高血压和/或高血压患者的受体共聚集物 肾脏疾病。二)解剖血管紧张素转换酶/血管加压素的生理作用 受体：2a)组织特异性、空间和时间表达模式 在开发AngiI/AVP受体基因方面，奠定了基础 用于评估其在集成生物实验系统中的功能 就像下面提出的基因打靶实验一样。2b)有针对性 阻断小鼠血管紧张素Ⅱ/血管紧张素Ⅱ受体基因以确定其 生理学在综合生物实验系统中的作用。这些 研究将阐明血管紧张素Ⅱ/精氨酸加压素受体的生理作用 并将Angii/AVP受体的状态定义为候选 高血压易感基因，从而为直接 该受体在盐敏感中的作用机制研究进展 高血压及其在高血压发病中的作用 有选择性的人类种群。

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.