Narrative review: the emerging clinical implications of the role of aldosterone in the metabolic syndrome and resistant hypertension

Abstract

The prevalence of obesity, diabetes, hypertension, and cardiovascular and chronic kidney disease is increasing in developed countries. Obesity, insulin resistance, and hypertension commonly cluster with other risk factors for cardiovascular and chronic kidney disease to form the metabolic syndrome. Emerging evidence supports a paradigm shift in our understanding of the renin-angiotensin-aldosterone system and in aldosterone's ability to promote insulin resistance and participate in the pathogenesis of the metabolic syndrome and resistant hypertension. Recent data suggest that excess circulating aldosterone promotes the development of both disorders by impairing insulin metabolic signaling and endothelial function, which in turn leads to insulin resistance and cardiovascular and renal structural and functional abnormalities. Indeed, hyperaldosteronism is associated with impaired pancreatic beta-cell function, skeletal muscle insulin sensitivity, and elevated production of proinflammatory adipokines from adipose tissue, which results in systemic inflammation and impaired glucose tolerance. Accumulating evidence indicates that the cardiovascular and renal abnormalities associated with insulin resistance are mediated in part by aldosterone acting on the mineralocorticoid receptor. Although we have known that mineralocorticoid receptor blockade attenuates cardiovascular and renal injury, only recently have we learned that mineralocorticoid receptor blockade improves pancreatic insulin release, insulin-mediated glucose utilization, and endothelium-dependent vasorelaxation. In summary, aldosterone excess has detrimental metabolic effects that contribute to the metabolic syndrome and endothelial dysfunction, which in turn contribute to the development of resistant hypertension as well as cardiovascular disease and chronic kidney disease.

Figure 1. Systemic effects of aldosterone on insulin sensitivity and hypertension

High salt intake, obesity, inactivity, and other environmental factors interact to activate the renin–angiotensin–aldosterone system, with subsequent inflammation and oxidative stress that drive maladaptive tissue responses. ACE = angiotensin-converting enzyme; ACTH = adrenocorticotropic hormone; Aldo = aldosterone; Ang I = angiotensin I; Ang II = angiotensin II; ASCVD = atherosclerotic cardiovascular disease; AT1 = angiotensin type 1 receptor; AT2 = angiotensin type 2 receptor; CAD = coronary artery disease; CHF = congestive heart failure; CRH = corticotropin-releasing hormone; LVH = left ventricular hypertrophy; MR = mineralocorticoid receptor; SNS = sympathetic nervous system.

Figure 2. Inhibitory actions of aldosterone and angiotensin II on insulin metabolic signaling in skeletal muscle

Aldosterone and angiotensin II mediate increases in inflammation and ROS that activate redox-sensitive serine kinases and contribute to impaired insulin metabolic signaling. Aldosterone and angiotensin II induce rapid maladaptive responses by stimulation of NADPH oxidase (step 1), thus generating ROS (step 2). An increase in ROS activates redox-sensitive serine kinase–signaling molecules (step 3) (5, 20-23). Reactive oxygen species–induced activation of these serine kinases induces phosphorylation of the serine moities of the IRS-1 docking protein (step 4). This serine phosphorylation of IRS-1 lessens its engagement with phosphatidylinositol 3-kinase (step 5), which leads to decreased activation of protein kinase B (step 6) and downstream metabolic effects, such as impaired glucose transport (step 7). AKT = protein kinase B; Aldo = aldosterone; AT = angiotensin; AT1R = angiotensin type 1 receptor; GLUT4 = glucose transport 4; IR = insulin receptor; MR = mineralocorticoid receptor; Mit = mitochondria; NADPH = nicotinamide ademine dinucleotide phosphate; P = phosphorus; PI3-K = phosphatidylinositol 3-kinase; R = renin; ROS = reactive oxygen species; Ser K = serine kinase; Tyr = tyrosine.