Adipocyte Renin-Angiotensin System and Programming of Hypertension

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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.