11β-Hydroxysteroid Dehydrogenases and Hypertension in the Metabolic Syndrome

Abstract

The metabolic syndrome describes a clustering of risk factors—visceral obesity, dyslipidaemia, insulin resistance, and salt-sensitive hypertension—that increases mortality related to cardiovascular disease, type 2 diabetes, cancer, and non-alcoholic fatty liver disease. The prevalence of these concurrent comorbidities is ~ 25–30% worldwide, and metabolic syndrome therefore presents a significant global public health burden. Evidence from clinical and preclinical studies indicates that glucocorticoid excess is a key causal feature of metabolic syndrome. This is not increased systemic in circulating cortisol, rather increased bioavailability of active glucocorticoids within tissues. This review examines the role of covert glucocorticoid excess on the hypertension of the metabolic syndrome. Here, the role of the 11β-hydroxysteroid dehydrogenase enzymes, which exert intracrine and paracrine control over glucocorticoid signalling, is examined. 11βHSD1 amplifies glucocorticoid action in cells and contributes to hypertension through direct and indirect effects on the kidney and vasculature. The deactivation of glucocorticoid by 11βHSD2 controls ligand access to glucocorticoid and mineralocorticoid receptors: loss of function promotes salt retention and hypertension. As for hypertension in general, high blood pressure in the metabolic syndrome reflects a complex interaction between multiple systems. The clear association between high dietary salt, glucocorticoid production, and metabolic disorders has major relevance for human health and warrants systematic evaluation.

Renal and Blood Pressure Response to a High-Salt Diet in Mice With Reduced Global Expression of the Glucocorticoid Receptor

“…The failure of neural and hormonal regulatory systems to adapt to high dietary salt intake is an important contributing factor to salt-sensitivity. In this context, sustained glucocorticoid excess, whether overt in Cushing’s or covert in Metabolic Syndrome, induces salt-sensitive hypertension and increases cardiovascular risk ( Bailey, 2017 ).…”

Molecular Mechanisms of Primary Aldosteronism

“…To achieve aldosterone-dependent response, the MR is protected from plasma glucocorticoid excess by corticosteroid 11-beta-dehydrogenase isozyme 2/11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) enzyme that converts cortisol to inactive cortisone. Action of 11ß-HSD2 creates glucocorticoid-free environment locally and makes MR action finely attuned to aldosterone concentration [15]. The role of aldosterone-MR complex in regulating homeostasis is mostly opposite to that of atrial natriuretic peptide (ANP) secreted by the heart.…”

Synthesis of Novel 2-(Isopropylamino)thiazol-4(5H)-one Derivatives and Their Inhibitory Activity of 11β-HSD1 and 11β-HSD2 in Aspect of Carcinogenesis Prevention

“…In turn, 11β-HSD2 is involved in carcinogenesis, tumor progression and metastasis along with its role in inflammation and hypertension regulation [ 18 , 19 ]. There are studies that have shown the promotion of tumor progression and metastasis by this enzyme, which may be due to its physiological function of inactivating glucocorticoids.…”