Adipocyte Renin-Angiotensin System and Programming of Hypertension

描述(申请人提供)：胎儿宫内发育受限的新生儿成年后患肥胖症、高血压和冠心病的风险增加。单单肥胖一项就占到了高血压的65%-78%。尽管这些关联的机制还不完全清楚，但脂肪组织显然是肥胖介导性高血压发生的关键因素。特别是，研究表明，脂肪衍生的血管紧张素原(AGT)可以贡献大约20%的血浆AGT浓度，并调节血压。肾素-血管紧张素系统(RAS)的所有成分都在脂肪组织中表达，肥胖者表现出脂肪RAS的上调，脂肪组织特异性AGT的过度表达会增加小鼠的血压和体脂，这一事实支持了这一事实。因此，成脂RAS可能是肥胖介导性高血压的潜在机制之一。利用母体食物限制(MFR)的大鼠模型，我们证明了MFR新生儿的生长受限，并降低了AGT和AT2的脂肪基因表达。当在哺乳期间允许追赶生长时，MFR后代发育成肥大的脂肪细胞，同时AGT、AT2和肾素的脂肪基因表达增加。这些MFR后代随后患上高血压和肥胖症，脂肪AGT、AT2和肾素持续上调。重要的是，在MFR成年后代中，血浆AGT水平升高，尽管肝脏AGT表达没有变化。这些发现提示脂肪RAS在MFR子代高血压表型中起重要作用。因此，我们建议研究脂肪RAS介导的MFR子代程序性高血压的机制。拟议的研究将系统地确定关键年龄时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，脂肪和全身性AGT的关系将被调查，并与血压和体脂相关。由于程序性成脂RAS也可能是细胞反应性增强的结果，我们将在体外检测分离的前期和成熟脂肪细胞对AGT激活剂/抑制剂的反应。此外，我们将确定妊娠程序性高血压与饮食诱导肥胖(DIO)介导高血压的机制。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，旨在抑制新生儿期成脂和随后的全身性RAS上调的干预策略将被用来防止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至关重要的。 与公共卫生相关成人和儿童的肥胖率上升了近50%。根据联邦标准的定义，目前约有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%。继发于营养或应激激素变化的胎儿生长受限会导致成年后的高血压。我们的孕妇在怀孕期间限制食物的模型会导致低出生体重的新生儿成年后患上肥胖症和高血压。潜在的原因可能是由于特定的内分泌系统(肾素-血管紧张素)的变化，该系统存在于脂肪组织中，在调节血压方面起着关键作用。因此，在肥胖患者，脂肪组织的增大可能会增强肾素-血管紧张素系统，从而导致血压升高。因此，我们建议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生中的作用。

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.