Adipocyte Renin-Angiotensin System and Programming of Hypertension

描述（由申请人提供）：宫内生长受限的新生儿患成人肥胖症、高血压和冠心病的风险增加。肥胖本身就占原发性高血压的65-78%。虽然这些相关性的机制还不完全清楚，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，脂肪来源的血管紧张素原（AGT）可以贡献约20%的血浆AGT浓度和调节血压。这得到以下事实的支持：肾素-血管紧张素系统（RAS）的所有组分在脂肪组织中表达，肥胖个体显示脂肪RAS的上调，并且脂肪组织特异性AGT过表达升高小鼠的血压和体脂。因此，脂肪形成RAS可能是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，我们已经证明了MFR新生儿生长受限，并减少了AGT和AT 2的脂肪基因表达。当允许在哺乳期追赶生长时，MFR后代发育肥大脂肪细胞，与AGT、AT 2和肾素的脂肪基因表达增加一致。这些MFR后代随后发展为高血压和肥胖，脂肪AGT、AT 2和肾素持续上调。重要的是，血浆AGT水平升高，但肝脏AGT表达在MFR成年后代中不变。这些发现表明脂肪RAS在MFR后代的高血压表型中起重要作用。因此，我们建议调查脂肪RAS介导的机制，程序性高血压的MFR后代。拟议的研究将系统地确定在划分肥胖-高血压表型进展的关键年龄的基底脂肪组织和血浆RAS组分。特别是，脂肪和全身AGT之间的关系将进行研究，并与血压和体脂。由于程序性脂肪形成RAS也可能是由增强的细胞反应性引起的，我们将研究分离的前成熟脂肪细胞和成熟脂肪细胞对AGT激活剂/抑制剂的体外反应。此外，我们将确定妊娠程序性肥胖与饮食诱导性肥胖（DIO）介导的高血压的机制。我们将进一步讨论性别（男性与女性）和脂肪储存（内脏与皮下）相关差异。最后，将使用旨在抑制新生儿期脂肪形成和随后全身RAS上调的干预策略来预防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是必要的。 公共卫生相关性成人和儿童的肥胖发生率上升了近50%。按照联邦标准的定义，今天大约30%的成年人和25%的儿童被认为是肥胖。重要的是，肥胖个体占高血压的70%。继发于营养或应激激素变化的胎儿生长受限导致成年后的高血压。我们的母亲在怀孕期间限制食物的模式导致低出生体重的新生儿，成年后发展为肥胖和高血压。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，该系统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-血管紧张素系统在生长受限新生儿成人高血压和肥胖发展中的作用。

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.