The Renin Angiotensin Aldosterone System in Obesity and Hypertension: Roles in the Cardiorenal Metabolic Syndrome

Abstract

In the United States, more than 50 million people have blood pressure at or above 120/80 mm Hg. All components of cardiorenal metabolic syndrome (CRS) are linked to metabolic abnormalities and obesity. A major driver for CRS is obesity. Current estimates show that many of those with hypertension and CRS show some degree of systemic and cardiovascular insulin resistance. Several pathophysiologic factors participate in the link between hypertension and CRS. This article updates recent literature with a focus on the function of insulin resistance, obesity, and renin angiotensin aldosterone system-mediated oxidative stress on endothelial dysfunction and the pathogenesis of hypertension.

Keywords: Adipocyte; Angiotensin II; Hypertension; Insulin resistance; Obesity.

Fig. 1

Coordinated influence of obesity, insulin resistance, activation of the RAAS and the SNS in the pathophysiology of hypertension in the CMS. Adapted from Manrique C, Lastra G, Gardner M, et al. The Renin Angiotensin Aldosterone System in Hypertension: Roles of Insulin Resistance and Oxidative Stress. Med Clin North Am 2009;93(3):569–82; with permission.

Fig. 2

(Upper inset) Vascular effects of insulin (INS) or insulin like growth factor (IGF)-1 and Counter regulatory effects of AT1R and MR activation in endothelial cells. Insulin actions on the blood vessel are partially mediated by increased production of NO through phosphorylation and secondary activation of endothelial NO synthase (eNOS). AT1R activation decreases the availability of NO by way of the induction of insulin resistance, diminishing eNOS mRNA stability, and promoting NADPH oxidase-induced ROS production. Mineralocorticoids also activate NAPDH oxidase with secondary O2– production and consequent generation of peroxinitrite (ONOO–). Akt, PI3K/protein kinase B; GRE, glucocorticoid response element; Gq, G_q subunit; IRS, insulin receptor substrate; NOX2, catalytic subunit of NADPH oxidase; p22, p47, p40, and p67, subunits of NADPH oxidase; PH, pleckstrin homology domain; PIP, phosphatidylinositol phosphate; PIP2, phosphatidylinositol bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; ROK, Rho kinase; SOD, superoxide dismutase. (Lower inset) Opposing effects of ANG II and aldosterone (Aldo) versus insulin/IGF-1 on VSMCs. Insulin and IGF-1 cause VSMC relaxation, whereas ANG II and mineralocorticoids cause contraction. MBS, myosin-bound serine; MLC, myosin light chain; MLCK, MLC kinase; Na/Ca exch, Na_/Ca2_ exchanger. From Manrique C, Lastra G, Gardner M, et al. The Renin Angiotensin Aldosterone System in Hypertension: Roles of Insulin Resistance and Oxidative Stress. Med Clin North Am 2009;93(3):569–82; with permission.