Aldosterone: Role in the Cardiometabolic Syndrome and Resistant Hypertension

Abstract 

The prevalence of diabetes, hypertension, and cardiovascular disease (CVD) and chronic kidney disease (CKD) is increasing in concert with obesity. Insulin resistance, metabolic dyslipidemia, central obesity, albuminuria. and hypertension commonly cluster to comprise the cardiometabolic syndrome (CMS). Emerging evidence supports a shift in our understanding of the crucial role of elevated serum aldosterone in promoting insulin resistance and resistant hypertension. Aldosterone enhances tissue generation of oxygen free radicals and systemic inflammation. This increase in oxidative stress and inflammation, in turn, contributes to impaired insulin metabolic signaling, reduced endothelial-mediated vasorelaxation, and associated cardiovascular and renal structural and functional abnormalities. In this context, recent investigation indicates that hyperaldosteronism, which is often associated with obesity, contributes to impaired pancreatic β-cell function as well as diminished skeletal muscle insulin metabolic signaling. Accumulating evidence indicates that the cardiovascular and renal abnormalities associated with insulin resistance are mediated, in part, by aldosterone's nongenomic as well as genomic signaling through the mineralocorticoid receptor (MR). In the CMS, there are increased circulating levels of glucocorticoids, which can also activate MR signaling in cardiovascular, adipose, skeletal muscle, neuronal, and liver tissue. Furthermore, there is increasing evidence that fat tissue produces a lipid soluble factor that stimulates aldosterone production from the adrenal zona glomerulosa. Recently, we have learned that MR blockade improves pancreatic insulin release, insulin-mediated glucose utilization, and endothelium-dependent vasorelaxation as well as reduces the progression of CVD and CKD. In summary, aldosterone excess exerts detrimental metabolic effects that contribute to the development of the CMS and resistant hypertension as well as CVD and CKD.

Abbreviations and Acronyms: ACE, angiotensin-converting enzyme, Ang II, angiotensin II, ARB, angiotensin type 1 receptor blocker, AT₁R, angiotensin type 1 receptor, BMI, body mass index, CKD, chronic kidney disease, CMS, cardiometabolic syndrome, CVD, cardiovascular disease, MR, mineralocorticoid receptor, NADPH, nicotinamide adenine dinucleotide phosphate, NO, nitric oxide, RAAS, renin-angiotensin-aldosterone, ROS, reactive oxygen species

Keywords: Aldosterone, Insulin resistance, Hypertension, Cardiometabolic syndrome