Mice with Brain‐Specific Deletion of Hsd11b2 have an impaired renal vascular and tubular response to high salt intake

Abstract

Loss‐of‐function mutations in Hsd11b2, the gene encoding the cortisol‐metabolising enzyme 11βHSD2, causes the hypertensive syndrome of Apparent Mineralocorticoid Excess. In affected individuals, overactivation of the mineralocorticoid receptor by cortisol is causative. Hypertension is salt‐sensitive, attributed to enhanced sodium reabsorption in the distal nephron and renal sodium retention. However, in the brain, 11βHSD2‐expressing neurons regulate salt appetite. We previously generated mice with conditional knockout of Hsd11b2 in the brain (Hsd11b2.BKO), which displayed enhanced salt preference and salt‐sensitive hypertension (DOI: 10.1161/CIRCULATIONAHA.115.019341). The mechanisms of salt‐sensitivity are unknown. In the current study we examined renal artery vasoreactivity and the in vivo acute pressure natriuresis response in male Hsd11b2.BKO mice and control littermates.Mice (n=10 per genotype/diet) were fed either high salt (3% Na) or 0.3% Na diet for 7 days. Animals were humanely killed, the renal arteries were isolated and mounted on a wire‐myograph to generate cumulative concentration‐response curves to phenylephrine and the nitric oxide donor, sodium nitroprusside. High salt diet significantly increased the sensitivity of the renal artery to phenylephrine‐induced vasoconstriction in Hsd11b2.BKO mice (LogEC50 0.3% diet ‐6.41±0.07 vs high salt ‐6.91±0.11; p=0.0013) but not in control mice. Sodium nitroprusside induced concentration‐dependent relaxation of renal arteries: the maximum relaxation was significantly reduced from 88±3% to 65±4% in Hsd11b2.BKO after high salt feeding (p<0.01); this was not seen in control mice. In other experiments, mice (n=5‐7 per genotype/diet) were anesthetised (thiobutabarbital sodium, 120mg/kg IP) and fractional renal sodium excretion was measured at baseline and following acutely increased blood pressure, achieved by sequential arterial ligation. In all mice, sodium excretion increased with blood pressure. In the high salt group, the pressure natriuresis response was significantly attenuated in Hsd11b2.BKO mice, compared to control animals.We find that genetic amplification of mineralocorticoid signalling in the brain attenuates the normal renal vascular and tubular adaptation to high salt intake. This regulation of renal salt excretion by the central nervous system may have implications for salt‐sensitive hypertension in humans.