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

• 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
• 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

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）：宫内生长限制的新生儿的成人肥胖，高血压和冠心病的风险增加。仅肥胖就占基本高血压的65-78％。尽管这些关联的基础机制尚未完全了解，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，脂肪衍生的血管紧张素原（AGT）可促成大约20％的血浆AGT浓度并调节血压。这是由以下事实支持的：肾素 - 血管紧张素系统（RAS）的所有组成部分均在脂肪组织中表达，肥胖个体表现出脂肪RAS的上调，而AGT的脂肪组织特异性过表达会增加小鼠的血压和体内脂肪。因此，成脂性RA可能是导致肥胖介导的高血压的潜在机制之一。使用母体食品限制的大鼠模型（MFR），我们证明了MFR新生儿受到生长的限制，并且降低了AGT和AT2的脂肪基因表达。当允许在护理期间追赶增长时，MFR后代会随着AGT，AT2和肾素的脂肪糖基因表达的增加而形成肥厚的脂肪细胞。这些MFR后代随后会出现高血压和肥胖，并持续上调脂肪AGT，AT2和肾素。重要的是，尽管MFR成人后代没有改变肝AGT表达，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的重要作用。因此，我们建议研究MFR后代中编程高血压的脂肪RAS介导的机制。拟议的研究将系统地确定临界年龄的基础脂肪组织和血浆RAS成分，以划分肥胖的高血压表型的进展。特别是，将研究脂肪与全身性AGT之间的关系，并与血压和体内脂肪相关。由于编程的脂肪生成性RA也可能是由于细胞反应增强而导致的，因此我们将检查分离的前和成熟脂肪细胞对AGT Ex-Vivo的激活剂/抑制剂的反应。此外，我们将确定妊娠程序编程与饮食诱导的（DIO）肥胖介导的高血压的机制。我们将进一步解决相关差异的性别（男性与女性）和脂肪仓库（内脏与皮下）的差异。最后，旨在抑制新生儿期间脂肪生成和随后的全身性RA的上调的介入策略将用于防止MFR高血压表型的发展。鉴于肥胖和高血压的急剧增加，尤其是在儿童中，了解MFR编程的高血压的机制和潜在预防策略的知识至关重要。 公共卫生相关性的成年人和儿童肥胖的发生率已上升近50％。根据联邦标准的定义，今天约有30％的成年人和25％的儿童被认为是肥胖的。重要的是，仅肥胖个体占高血压的70％。胎儿生长限制继发于营养或压力荷尔蒙变化导致成人生活中的高血压。我们在怀孕期间的孕产妇限制模型导致新生儿低出生体重，成年后会产生肥胖和高血压。根本原因可能是由于特定内分泌系统（肾素 - 血管紧张素）的变化所致，该系统存在于脂肪组织中，并且在调节血压中起着关键作用。因此，在肥胖症中，脂肪组织的大小增加可能会增强肾素 - 血管紧张素系统，然后导致血压升高。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年高血压和肥胖症发展中的作用。