ANGIOTENSIN RECEPTOR GENES AND BLOOD PRESSURE REGULATION

血管紧张素受体基因和血压调节

• 批准号: 2638066
• 负责人: THOMAS M COFFMAN
• 金额: $ 19.85万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-01 至 1999-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2638066
• 关键词: angiotensin II; angiotensins; blood pressure; electrolyte balance; gene targeting; genetic regulation; genetically modified animals; hormone receptor; ion transport; laboratory mouse; nutrition related tag; receptor sensitivity; renal tubular transport; renin angiotensin system; salt intake

DESCRIPTION: The renin-angiotensin system (RAS) plays a critical role in regulating blood pressure and sodium balance and these actions are mediated through angiotensin type I (AT1) receptors. In the kidney, the RAS acts through three distinct pathways that may influence sodium handling: (1) hemodynamic effects at the level of the glomerular circulation mediated by ATl receptors on renal vasculature (2) direct effects on sodium transport modulated by ATl receptors expressed on proximal tubular epithelial cells (3) regulation of sodium reabsorption in the distal nephron by aldosterone under the control of ATl receptors in the adrenal cortex. In the mouse, two separate ATl receptor genes control these functions: AgtrlA and AgtrlB. Using mouse models in which expression of these ATl receptor genes has been specifically altered using gene targeting, it is proposed to determine the role of ATl angiotensin receptor genes in regulating blood pressure through the following specific aims: Specific Aim I: To define the role of the ATlA receptor in renal adaptation to altered dietary sodium intake, the hypothesis that abnormal renal sodium handling contributes to sodium dependent blood pressure changes in the AgtrlA (-/-) mice will be studied. Specific Aim II: To examine the role of renal AgtrlA expression in the regulation of blood pressure, the contribution of renal ATlA receptors to the control of blood pressure in renal cross transplantation experiments between AgtrlA (+/+) and AgtrlA (-/-) mice will be determined. Specific Aim III: To determine the contribution of renal epithelial actions of angiotensin II to blood pressure and sodium homeostasis transgenic mice that express the ATlA receptor in the kidney only on epithelial cells in the proximal tubule will be developed. Specific Aim IV: To determine the role of AT1B receptors in blood pressure regulation in AgtrlA (-/-) mice, RAS regulation by dietary sodium, and blood pressure responses will be studied when AT1B receptors are inhibited or absent. Specific Aim V: To define the contribution of the AgtrlB gene to blood pressure regulation, mice with targeted disruption of the AgtrlB gene will be studied.

描述：肾素-血管紧张素系统(RAS)在 调节血压和钠平衡，这些作用是通过 通过血管紧张素I型(AT1)受体。在肾脏，RAS起作用 通过三条不同的途径可能影响钠的处理：(1) 在肾小球循环水平上的血流动力学效应 肾血管ATL受体(2)对钠转运的直接作用 近端肾小管上皮细胞表达ATL受体的调控 (3)醛固酮对远端肾单位钠重吸收的调节 在肾上腺皮质ATL受体的控制下。在老鼠身上，有两个 不同的ATL受体基因控制这些功能：AgtrlA和AgtrlB。 使用表达这些ATL受体基因的小鼠模型 利用基因打靶进行特定的改变，建议确定 AT1血管紧张素受体基因在血压调节中的作用 以下具体目标：具体目标一：界定 ATLA受体在肾脏对饮食钠摄入量改变的适应中的作用 肾脏钠处理异常导致钠的假说 将研究AgtrlA(-/-)小鼠的依赖性血压变化。 目的II：探讨肾脏AgtrlA表达在慢性肾小球疾病中的作用。 血压的调节，肾脏ATLA受体的作用 肾交叉移植实验中的血压控制 将确定AgtrlA(+/+)和AgtrlA(-/-)小鼠之间的差异。特定目标 III：确定肾上皮细胞作用的贡献 血管紧张素II对血压和钠稳态转基因小鼠的影响 ATLA受体在肾脏中仅在肾小管上皮细胞上表达 近端小管将被发育。具体目标四：确定角色 AT1B受体在AgtrlA(-/-)小鼠血压调节中的作用 饮食钠的调节和血压反应将被研究 当AT1B受体被抑制或缺失时。具体目标五：定义 AgtrlB基因在血压调节中的作用 对AgtrlB基因的靶向破坏将进行研究。