Abstract
The clinical manifestations of glucocorticoid excess include central obesity, hyperglycaemia, dyslipidaemia, electrolyte abnormalities and hypertension. A century on from Cushing's original case study, these cardinal features are prevalent in industrialized nations. Hypertension is the major modifiable risk factor for cardiovascular and renal disease and reflects underlying abnormalities of Na+ homeostasis. Aldosterone is a master regulator of renal Na+ transport but here we argue that glucocorticoids are also influential, particularly during moderate excess. The hypothalamic–pituitary–adrenal axis can affect renal Na+ homeostasis on multiple levels, systemically by increasing mineralocorticoid synthesis and locally by actions on both the mineralocorticoid and glucocorticoid receptors, both of which are expressed in the kidney. The kidney also expresses both of the 11β-hydroxysteroid dehydrogenase (11βHSD) enzymes. The intrarenal generation of active glucocorticoid by 11βHSD1 stimulates Na+ reabsorption; failure to downregulate the enzyme during adaption to high dietary salt causes salt-sensitive hypertension. The deactivation of glucocorticoid by 11βHSD2 underpins the regulatory dominance for Na+ transport of mineralocorticoids and defines the ‘aldosterone-sensitive distal nephron’. In summary, glucocorticoids can stimulate renal transport processes conventionally attributed to the renin–angiotensin–aldosterone system. Importantly, Na+ and volume homeostasis do not exert negative feedback on the hypothalamic–pituitary–adrenal axis. These actions are therefore clinically relevant and may contribute to the pathogenesis of hypertension in conditions associated with elevated glucocorticoid levels, such as the metabolic syndrome and chronic stress.
Highlights
It is over 100 years since Harvey Cushing described the clinical consequences of severe glucocorticoid excess (Cushing, 1912) and this syndrome remains rare, the cardinal features of central obesity, dyslipidaemia, impaired glucose metabolism and hypertension are increasingly prevalent in Western society
Jessica has a First Class degree in Pharmacology and an MSc with Distinction in Cardiovascular Biology, both from the University of Edinburgh. Her PhD combines in vivo approaches for cardiovascular and renal physiology with molecular techniques to explore the contribution of glucocorticoid excess to salt-sensitive hypertension
The widespread therapeutic use of glucocorticoid receptor (GR) agonists may flatten the dynamic regulation of the HPAA with deleterious consequences for renal Na+ homeostasis
Summary
It is over 100 years since Harvey Cushing described the clinical consequences of severe glucocorticoid excess (Cushing, 1912) and this syndrome remains rare, the cardinal features of central obesity, dyslipidaemia, impaired glucose metabolism and hypertension are increasingly prevalent in Western society Her PhD combines in vivo approaches for cardiovascular and renal physiology with molecular techniques to explore the contribution of glucocorticoid excess to salt-sensitive hypertension. Knockdown of 11βHSD1 expression/activity was induced by injecting siRNA into the renal medulla in vivo: hsd11b1 knockdown attenuated salt-sensitive hypertension in the DSS rats (Liu et al 2008).
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