Adipocyte Renin-Angiotensin System and Programming of Hypertension

脂肪细胞肾素-血管紧张素系统与高血压的规划

基本信息

批准号：
7571541
负责人：
Mina Desai
金额：
$ 6.9万
依托单位：
LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-01 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7571541
关键词：
AGTR2 gene Accounting Address Adipocytes Adipose tissue Adult Adult Children Age Angiotensin II Angiotensin II Receptor Angiotensinogen Angiotensins Blood Pressure Body fat Cell physiology Child Coronary heart disease Data Development Diet Discipline of Nursing Endocrine system Essential Hypertension Exhibits Fatty acid glycerol esters Female Fetal Growth Fetal Growth Retardation Gender Gene Expression Growth Hormonal Change Hypertension Incidence Individual Intervention Knowledge Lead Life Liver Low Birth Weight Infant Maternal Age Mediating Messenger RNA Modeling Molecular Biology Mus Neonatal Newborn Infant Nutritional Obesity Phenotype Physiology Plasma Play Pregnancy Prevention Prevention strategy Rattus Renin Renin-Angiotensin System Risk Role Secondary to Series Stress Systems Analysis Techniques Up-Regulation Visceral food restriction inhibitor/antagonist insight mRNA Expression male offspring overexpression prevent programs protein expression public health relevance receptor research study response subcutaneous

项目摘要

DESCRIPTION (provided by applicant): Intrauterine growth restricted newborns have an increased risk of adult obesity, hypertension and coronary heart disease. Obesity alone accounts for 65-78% of essential hypertension. Although the mechanisms underlying these associations are not fully understood, adipose tissue clearly is a critical factor in the development of obesity- mediated hypertension. In particular, studies have shown that adipose-derived angiotensinogen (AGT) can contribute to approximately 20% of plasma AGT concentrations and modulate blood pressure. This is supported by the fact that all components of renin-angiotensin system (RAS) are expressed in adipose tissue, obese individuals show upregulation of adipose RAS, and adipose tissue-specific overexpression of AGT raises blood pressure and body fat in mice. Thus, adipogenic RAS may be one of the underlying mechanisms contributing to obesity-mediated hypertension. Using a rat model of maternal food restriction (MFR), we have demonstrated that MFR newborns are growth restricted, and have reduced adipose gene expression of AGT and AT2. When allowed catch-up growth during the nursing period, the MFR offspring develop hypertrophic adipocytes in concert with increased adipose gene expression of AGT, AT2 and renin. These MFR offspring subsequently develop hypertension and obesity with persistently upregulated adipose AGT, AT2 and renin. Importantly, plasma AGT levels are elevated though liver AGT expression is unchanged in MFR adult offspring. These findings suggest an important role of adipose RAS in the hypertensive phenotype of MFR offspring. We thus propose to investigate the adipose RAS mediated mechanism of programmed hypertension in MFR offspring. The proposed studies will systematically determine the basal adipose tissue and plasma RAS components at critical ages that demarcate the progression of the obese- hypertensive phenotype. In particular, the relationship between adipose and systemic AGT will be investigated and correlated with blood pressure and body fat. As programmed adipogenic RAS may also result from enhanced cellular responsiveness, we will examine the response of isolated pre- and mature adipocytes to activators/inhibitors of AGT ex-vivo. Additionally, we will determine the mechanism of gestationally programmed versus diet-induced (DIO) obesity mediated hypertension. We will further address gender (male versus female) and fat depot (visceral versus subcutaneous) related differences. Finally, interventional strategy aimed at suppressing the upregulation of adipogenic and subsequently systemic RAS during the neonatal period will be used to prevent the development of the MFR hypertensive phenotype. In view of the dramatic increase in obesity and hypertension, especially in children, knowledge of the mechanism and potential prevention strategy for MFR programmed hypertension is essential. PUBLIC HEALTH RELEVANCE The incidence of obesity among adults and children has risen nearly 50 percent. As defined by federal standards, approximately 30 percent of adults and 25 percent of children are considered obese today. Importantly, obese individuals alone accounts for 70% of hypertension. Fetal growth restriction secondary to nutritional or stress hormonal changes results in hypertension in adult life. Our model of maternal food restriction during pregnancy results in low birth weight newborns that develop obesity and hypertension as adults. The underlying cause may be due to changes in a specific endocrine system (renin-angiotensin) which is present in adipose tissue and plays a key role in regulating blood pressure. Therefore in obesity, the increased size of adipose tissue may enhance the renin-angiotensin system and subsequently lead to increased blood pressure. Our proposed studies will therefore determine the role of adipose renin-angiotensin system in development of adult hypertension and obesity in growth restricted newborns.

描述（由申请人提供）：宫内生长受限的新生儿患成人肥胖、高血压和冠心病的风险增加。仅肥胖就占原发性高血压的 65-78%。尽管这些关联的机制尚不完全清楚，但脂肪组织显然是肥胖介导的高血压发展的关键因素。特别是，研究表明，脂肪源性血管紧张素原 (AGT) 约占血浆 AGT 浓度的 20%，并可调节血压。肾素-血管紧张素系统 (RAS) 的所有成分均在脂肪组织中表达，肥胖个体显示脂肪 RAS 上调，并且脂肪组织特异性 AGT 过度表达会升高小鼠的血压和体脂，这一事实支持了这一点。因此，脂肪生成 RAS 可能是导致肥胖介导的高血压的潜在机制之一。使用母体食物限制 (MFR) 的大鼠模型，我们证明 MFR 新生儿生长受限，并且 AGT 和 AT2 的脂肪基因表达降低。当在哺乳期允许追赶生长时，MFR后代会发育肥大的脂肪细胞，同时AGT、AT2和肾素的脂肪基因表达增加。这些 MFR 后代随后会出现高血压和肥胖症，并且脂肪 AGT、AT2 和肾素持续上调。重要的是，尽管 MFR 成年后代的肝脏 AGT 表达没有变化，但血浆 AGT 水平升高。这些发现表明脂肪 RAS 在 MFR 后代的高血压表型中发挥重要作用。因此，我们建议研究 MFR 后代中脂肪 RAS 介导的程序性高血压的机制。拟议的研究将系统地确定关键年龄的基础脂肪组织和血浆 RAS 成分，以区分肥胖高血压表型的进展。特别是，将研究脂肪和全身 AGT 之间的关系，并将其与血压和体脂相关。由于程序性脂肪形成 RAS 也可能是由于细胞反应性增强所致，因此我们将在体外检查分离的前脂肪细胞和成熟脂肪细胞对 AGT 激活剂/抑制剂的反应。此外，我们将确定妊娠程序性肥胖与饮食诱导（DIO）肥胖介导的高血压的机制。我们将进一步解决性别（男性与女性）和脂肪库（内脏与皮下）相关的差异。最后，旨在抑制新生儿期脂肪生成和随后的全身 RAS 上调的干预策略将用于预防 MFR 高血压表型的发展。鉴于肥胖和高血压的急剧增加，特别是在儿童中，了解 MFR 程序性高血压的机制和潜在的预防策略至关重要。公共卫生相关性成人和儿童的肥胖发生率上升了近 50%。根据联邦标准的定义，当今大约 30% 的成年人和 25% 的儿童被认为肥胖。重要的是，仅肥胖者就占高血压的 70%。继发于营养或压力荷尔蒙变化的胎儿生长受限会导致成年后高血压。我们的母亲在怀孕期间限制食物的模式会导致出生体重低的新生儿，成年后会出现肥胖和高血压。根本原因可能是由于脂肪组织中存在的特定内分泌系统（肾素-血管紧张素）的变化，在调节血压方面发挥着关键作用。因此，在肥胖症中，脂肪组织尺寸的增加可能会增强肾素-血管紧张素系统，从而导致血压升高。因此，我们提出的研究将确定脂肪肾素-血管紧张素系统在成人高血压和生长受限新生儿肥胖中的作用。