Glucocorticoids and renal Na⁺ transport: implications for hypertension and salt sensitivity

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.

Dexamethasone‐induced diuresis is associated with inhibition of the renin–angiotensin–aldosterone system in rats

“…Subsequently, RAAS activation elevates circulating ANG II and aldosterone levels leading to the decongesting effects of diuresis, and impairing renal function [2,4]. Corticosteroids demonstrably induce potent diuresis in animals and HF patients [5–13]. However, because the effects of corticosteroids on RAAS activation are unclear, we induced chronic HF (CHF) in rats and examined the effects of water restriction (WR) and dexamethasone (Dex) on RAAS activity.…”

Hypertrophy in the Distal Convoluted Tubule of an 11β-Hydroxysteroid Dehydrogenase Type 2 Knockout Model

“…Because the DCT expresses both the MR and glucocorticoid receptor, Na + transport is not likely to be regulated solely by the canonical aldosterone signaling pathways present in principal cells; glucocorticoids may exert a stronger influence here than in the CNT and CCD. 42,43 It is pertinent that NCC is regulated by the SGK1/Nedd4-2 pathway in DCT cells. 6 Although this is a classic target of MR signaling, this pathway may also be activated by glucocorticoids.…”

Matrix metalloproteinase‐9, 10, and stress hyperglycaemia in acute kidney injury

“…There exist several explanations of the relationship between stress hyperglycaemia and AKI. [20][21][22] Furthermore, stress hyperglycaemia may induce osmotic diuresis, resulting in the reduction in volume and increased risk of prerenal azotemia as well as AKI. The defective insulin secretion worsens hyperglycaemia, in particular, in CKD population.…”