Blood pressure response to angiotensin II is enhanced in obese Zucker rats and is attributed to an aldosterone-dependent mechanism

Obesity, which has become a problem of epidemic proportions in Western countries, is frequently accompanied by hypertension and an increased incidence of cardiovascular mortality. Data from the Framingham Offspring Study suggest that 65–75% of the risk for hypertension can be attributed to an excess of abdominal fat mass (Garrison et al., 1987). The mechanisms by which fat mass leads to hypertension are not fully known. Several central and peripheral abnormalities that can explain the development or maintenance of high arterial pressure in obesity have been identified, among these are hormonal systems and also the sympathetic nervous system (Rahmouni et al., 2005). In the last decade, it has become apparent that adipose tissue is a prolific organ that secretes several immunomodulators and bioactive molecules, which have been implicated in promoting obesity hypertension (Hutley and Prins, 2005). Historically, activation of the renin–angiotensin–aldosterone system (RAAS) has been established as a major determinant of BP, and there is evidence that the RAAS may constitute an important link between obesity and hypertension. With respect to obesity, the RAAS has been shown to be activated in fat tissue of rats and human patients (Giacchetti et al., 2002; Boustany et al., 2004; Engeli et al., 2005). In addition, obesity has been found to be associated with an up-regulation of ACE in adipocytes (Bloem et al., 1995; Cooper et al., 1998; Karlsson et al., 1998), as well as with increased levels of circulating angiotensin II (AngII) (Harte et al., 2005). When body weight is reduced in obese women, plasma levels of renin, AGT, and aldosterone and plasma ACE activity are normalized, a phenomenon that is also associated with a reduction in BP (Engeli et al., 2005). Aldosterone, another key player in the RAAS, also correlates positively with obesity (Lamounier-Zepter et al., 2005; Krug and Ehrhart-Bornstein, 2008), suggesting a link between obesity-associated hypertension and increased mineralocorticoid levels. Indeed, a recent study in African-Americans verified that BP correlates positively with plasma aldosterone levels, and the latter correlates significantly with waist circumference, total cholesterol, triglycerides, insulin and the insulin-resistance index (Kidambi et al., 2007). From a mechanistic point of view, AngII has been shown to regulate the secretion of aldosterone from adrenal glands in an autocrine/paracrine manner; it not only stimulates aldosterone release in human adrenocarcinoma cells, but AngII is also produced in these cells (Hilbers et al., 1999). Adipocyte secretory products also increase aldosterone release (Ehrhart-Bornstein et al., 2003; 2004), but this process seems to be independent of adipose tissue AngII as AT1 receptor blockade did not diminish aldosterone secretion induced by fat cell-conditioned medium (Ehrhart-Bornstein et al., 2003). However, the Ehrhart–Bornstein group demonstrated that adipocytes not only secrete mineralocorticoid-stimulating factors but also sensitize adrenocortical cells to AngII. In addition, they found that this sensitization of adrenocortical cells to stimulation by AngII is possibly mediated via ERK1/2-dependent up-regulation of steroidogenic acute regulatory protein (StAR) activity (Krug et al., 2007). Indeed, in a clinical study it was established that AngII-mediated aldosterone secretion is higher in obese than in lean patients, confirming these experimental findings (Bentley-Lewis et al., 2007). This indicates that the adrenal glands of overweight individuals are hypersensitive. As outlined above, AngII and aldosterone are both increased in obese individuals; moreover, blood aldosterone is higher in overweight subjects after AngII infusion (Bentley-Lewis et al., 2007). This indicates a sensitization of the adrenals to AngII. This conclusion is also supported by findings showing an increased corticosterone response during stress in obese rats after chronic AngII (Muller et al., 2007). Since aldosteronogenesis in obesity has been demonstrated to be caused not only by AngII but also by other adipocyte-derived factors, such as oxidized fatty acids (Goodfriend et al., 2004), and it is still not known whether AngII-induced increase in BP is also indirectly associated with the hypertensive potency of aldosterone, we investigated the contribution of aldosterone to the hypertensive response induced by chronic AngII administration to obese rats. We tested our hypothesis using Zucker rats, which serve as a genetic animal model for leptin resistance. Zucker rats become obese, hyperphagic and hyperleptinaemic (OZR) due to a homozygous point mutation in the leptin receptor. Zucker rats with only a heterozygous mutation remain lean (LZR). The simple fact that Zucker rats are obese but not inevitably hypertensive means that this strain can serve as an experimental animal model to study whether the BP response to chronic AngII is enhanced during obesity and to determine the involvement of aldosterone in this response. In addition, the involvement of aldosterone in obesity-induced hypertension was investigated in a rat model of diet-induced obesity (DIO).