ANGIOTENSIN RECEPTOR GENES AND BLOOD PRESSURE REGULATION

血管紧张素受体基因和血压调节

• 批准号: 2857874
• 负责人: THOMAS M COFFMAN
• 金额: $ 20.45万
• 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/2857874
• 关键词: angiotensin II; angiotensin receptor; angiotensins; blood pressure; electrolyte balance; gene targeting; genetic regulation; genetically modified animals; 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：血管紧张素系统（RAS）在以下方面发挥着关键作用 调节血压和钠平衡， 通过血管紧张素I型（AT 1）受体。 在肾脏中，RAS作用于 通过三种不同的途径可能影响钠的处理：（1） 在肾小球循环水平的血液动力学效应， 肾血管上的AT 1受体（2）对钠转运的直接作用 由近端肾小管上皮细胞上表达的AT 1受体调节 (3)醛固酮对远端肾单位钠重吸收的调节 在肾上腺皮质中的AT 1受体的控制下。 在小鼠中，两个 单独的AT 1受体基因控制这些功能：AgtrlA和AgtrlB。 使用小鼠模型，其中这些AT 1受体基因的表达已经被抑制。 特别是使用基因靶向改变，建议确定 AT 1血管紧张素受体基因在调节血压中的作用 具体目标一：确定联合国的作用， AT 1A受体在肾脏适应改变饮食钠摄入中的作用 肾钠处理异常有助于钠 将研究AgtrlA（-/-）小鼠中的依赖性血压变化。 具体目的II：研究肾脏AgtrlA表达在肾移植中的作用。 调节血压，肾AT 1A受体对血压的贡献， 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。 具体目标 III：为了确定肾上皮细胞作用的贡献， 血管紧张素II对血压和钠稳态的转基因小鼠， 在肾脏中仅在上皮细胞上表达AT 1A受体， 近端小管将发育。 具体目标四：确定作用 AT 1B受体在AgtrlA（-/-）小鼠血压调节中的作用 调节饮食钠，血压反应将进行研究 当AT 1B受体被抑制或缺失时。 具体目标五： AgtrlB基因对血压调节的贡献， 将研究AgtrlB基因的靶向破坏。