Angiotensin: A Link Between Obesity and Hypertension

血管紧张素：肥胖和高血压之间的联系

• 批准号: 6753554
• 负责人: Lisa A Cassis
• 金额: $ 47.07万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-03 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6753554
• 关键词: adipocytes; angiotensin /renin /aldosterone hypertension; angiotensin II; autoradiography; blood pressure; dietary lipid; high performance liquid chromatography; hypertension; laboratory mouse; laboratory rat; messenger RNA; obesity; polymerase chain reaction; renin angiotensin system

DESCRIPTION (provided by applicant): The proposed studies are in response to RFA-HL-02-016 and will address the working hypothesis that a moderately high fat diet (MHF) stimulates the adipose renin-angiotensin system, contributing to obesity-related elevations in blood pressure. Preliminary data demonstrates that rats fed a MHF diet segregate into obesity prone (OP) versus obesity-resistant (OR) populations. In OP rats, blood pressure was increased coincident with activation of the systemic and adipose renin-angiotensin system. The first hypothesis is that a MHF diet activates the adipose renin-angiotensin system, resulting in an increase in circulating angiotensin peptides and blood pressure. Time-dependent regulation of adipose versus non-adipose components of the renin-angiotensin system will be examined in control, OR and OP rats and compared to the time course for elevations in blood pressure. The contribution of various circulating angiotensin peptides to blood pressure elevations in control, OR and OP rats will be determined. The second hypothesis is that adipocytes from OP rats exhibit a redistribution of free cholesterol from the plasma membrane to intracellular triglyceride pools, thereby increasing the activity of sterol regulatory binding protein-2 and stimulating angiotensinogen (Ao) mRNA expression. This would provide an adipocyte-specific mechanism for regulation of Ao gene expression in response to the MHF diet. The intracellular localization of free cholesterol in adipocytes prepared from control, OR and OP rats will be determined and compared to the level of Ao mRNA expression. The effect of depletion of intracellular free cholesterol pools on adipocyte Ao mRNA expression will be determined. The third hypothesis is that elevations in circulating angiotensin peptides increase blood pressure in OP rats by stimulating sympathetic drive. The responsiveness of the baroreceptor reflex and the blood pressure response to ganglionic blockade will be determined in control, OR and OP rats. A second approach will determine the effect of neonatal sympathectomy on blood pressure elevations in diet-induced obesity. In hypothesis 4 a novel animal model will be developed to determine the effect of targeted deficiency of Ao in adipose tissue on blood pressure regulation in diet-induced obesity. The goals of this research are to definitively determine the role of adipose-derived angiotensins and the systemic renin-angiotensin system in blood pressure elevations in diet-induced obesity.

描述（由申请人提供）： 拟议的研究是针对 RFA-HL-02-016 的回应，并将解决以下假设：中度高脂肪饮食 (MHF) 会刺激脂肪肾素-血管紧张素系统，导致肥胖相关的血压升高。 初步数据表明，饲喂 MHF 饮食的大鼠分为易肥胖 (OP) 群体和抗肥胖 (OR) 群体。 在OP大鼠中，血压随着全身和脂肪肾素-血管紧张素系统的激活而升高。 第一个假设是，MHF 饮食会激活脂肪肾素-血管紧张素系统，导致循环血管紧张素肽和血压升高。 将在对照大鼠、OR大鼠和OP大鼠中检查肾素-血管紧张素系统的脂肪与非脂肪成分的时间依赖性调节，并与血压升高的时间过程进行比较。 将确定各种循环血管紧张素肽对对照、OR和OP大鼠血压升高的影响。 第二个假设是，OP 大鼠的脂肪细胞表现出游离胆固醇从质膜到细胞内甘油三酯库的重新分配，从而增加甾醇调节结合蛋白-2 的活性并刺激血管紧张素原 (Ao) mRNA 表达。 这将为调节 Ao 基因表达以响应 MHF 饮食提供脂肪细胞特异性机制。 将测定从对照、OR和OP大鼠制备的脂肪细胞中游离胆固醇的细胞内定位并与Ao mRNA表达水平进行比较。 将测定细胞内游离胆固醇库的消耗对脂肪细胞Ao mRNA表达的影响。 第三个假设是，循环血管紧张素肽的升高通过刺激交感神经驱动而增加 OP 大鼠的血压。 将在对照、OR和OP大鼠中测定压力感受器反射的反应性和血压对神经节阻滞的反应。 第二种方法将确定新生儿交感神经切除术对饮食引起的肥胖症血压升高的影响。在假设 4 中，将开发一种新的动物模型来确定脂肪组织中 Ao 的靶向缺乏对饮食引起的肥胖症的血压调节的影响。 这项研究的目标是明确确定脂肪源性血管紧张素和全身肾素-血管紧张素系统在饮食引起的肥胖血压升高中的作用。