HSD11B2 encodes the glucocorticoid-metabolising enzyme 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2), which in is mainly expressed in the principal cell of the aldosterone-sensitive distal nephron. Loss of function mutations cause the rare hypertensive Syndrome of Apparent Mineralocorticoid Excess. Overactivation of the mineralocorticoid receptor by endogenous glucocorticoid is causative (Bailey, 2017). Hypertension is salt-sensitive, attributed to enhanced ENaC-mediated sodium reabsorption and renal sodium retention (Mullins et al, 2015). However, 11βHSD2 is also expressed in a subset of neurons in the nucleus of the solitary tract that regulate the behavioural drive to consume salt in rodents (Geerling & Loewy, 2008). We used a cre-lox approach to generate mice with conditional knockout of Hsd11b2 in the brain (Hsd11b2.BKO). These mice had >90% knockdown of 11βHSD2 activity in the brainstem and displayed enhanced salt appetite and salt-sensitive hypertension (Evans et al, 2016). The mechanisms of salt-sensitivity are unknown and here we examined renal sodium excretion in male Hsd11b2.BKO mice and control littermates.

Mice (n=5-8) mice per genotype/diet were fed diets containing either 0.3% (control) or 3% sodium by weight for 7-10 days. Urine was collected for 24h and mice were then anaesthetised (thiobutabarbital sodium, 120mg/kg IP) and instrumented for measurement of renal function. Sodium excretion was measured at baseline and then again following ligation of peripheral arteries to acutely raise arterial blood pressure by ~15mmHg. At the end of the experiment, a blood sample for measurement of aldosterone and mice then killed. Data are shown as mean±SD and comparisons were by t-test or two-way ANOVA.

High salt diet significantly reduced plasma aldosterone in control mice (634±201pg/ml vs 115±35pg/ml; p<0.001). In Hsd11b2.BKO mice, aldosterone was already supressed on control diet and was the further reduced induced by high salt intake (131±66pg/ml vs 60±14pg/ml) was not statistically significant. In all mice, urinary sodium excretion was increased by high salt intake. However, sodium excretion was significantly lower in Hsd11b2.BKO mice than in controls after high salt feeding. Urinary excretion of 8-isoprostane was measured as a marker of production of reactive oxygen species in the kidney. This was not significantly affected by high salt diet in control mice (3.29±2.33 vs 4.22±2.68 ng/24h). In Hsd11b2.BKO mice, high salt significantly increased 8-isoprostane excretion (2.43±2.87 vs 12.21±5.52; p<0.01). In the anaesthetised preparation, sodium excretion rate was not different between genotypes. The acute elevation in arterial blood pressure increased fractional sodium excretion fourfold in control mice (p<0.01), indicative of down-regulation of tubular epithelial sodium reabsorption. In Hsd11b2.BKO mice, the pressure-induced natriuresis was not statistically significant (1.3±0.7 vs 1.8+0.9mmol/min).  

Deletion of Hsd11b2 in the brain amplifies leads to suppression of aldosterone production. Despite this, the normal renal tubular adaptation to high salt intake is compromised. This may reflect enhanced production of reactive oxygen species.