Sodium homeostasis is preserved in a global 11β-hydroxysteroid dehydrogenase type 1 knockout mouse model

What is the central question of this study? Glucocorticoids act in the kidney to promote salt and water retention. Renal 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1), by increasing local concentrations of glucocorticoids, may exert an antinatriuretic effect. We hypothesized that global deletion of 11βHSD1 in the mouse would give rise to a salt-wasting renal phenotype. What is the main finding and its importance? We subjected a mouse model of global 11βHSD1 deletion to studies of water and electrolyte balance, renal clearance, urinary steroid excretion, renin-angiotensin system activation and renal sodium transporter expression. We found no significant effects on renal sodium or water excretion. Any effect of renal 11βHSD1 on sodium homeostasis is subtle. Glucocorticoids act in the kidney to regulate glomerular haemodynamics and tubular sodium transport; the net effect favours sodium retention. 11β-Hydroxysteroid dehydrogenase type 1 (11βHSD1) is expressed in the renal tubules and the interstitial cells of the medulla, where it is likely to regenerate active glucocorticoids from inert 11-keto forms. The physiological function of renal 11βHSD1 is largely unknown. We hypothesized that loss of renal 11βHSD1 would result in salt wasting and tested this in a knockout mouse model in which 11βHSD1 was deleted in all body tissues. In balance studies, 11βHSD1 deletion had no effect on water, sodium or potassium metabolism; transition to a low-sodium diet did not reveal a natriuretic phenotype. Renal clearance studies demonstrated identical haemodynamic parameters (arterial blood pressure, renal blood flow and glomerular filtration rate) in knockout and wild-type mice, but revealed an augmented kaliuretic response to thiazides in 11βHSD1 knockout animals. There was no effect on the natriuretic response to the amiloride analogue benzamil. Urinary excretion of deoxycorticosterone was higher in 11βHSD1 knockout mice, and there was hypertrophy of cells in the zona fasciculata of the adrenal cortex. There was no difference in the activity of the renin-angiotensin and nitric oxide systems, no difference in renal histology and no difference in the abundance of key tubular transporter proteins. We conclude that any effect of 11βHSD1 on renal sodium excretion is subtle.