A urine-concentrating defect in 11β-hydroxysteroid dehydrogenase type 2 null mice

Abstract

In aldosterone target tissues, 11␤-hydroxysteroid dehydrogenase type 2 (11␤HSD2) is coexpressed with mineralocorticoid receptors (MR) and protects the receptor from activation by glucocorticoids. Null mutations in the encoding gene, HSD11B2, cause apparent mineralocorticoid excess, in which hypertension is thought to reflect volume expansion secondary to sodium retention. Hsd11b2 Ϫ/Ϫ mice are indeed hypertensive, but impaired natriuretic capacity is associated with significant volume contraction, suggestive of a urine concentrating defect. Water turnover and the urine concentrating response to a 24-h water deprivation challenge were therefore assessed in Hsd11b2 Ϫ/Ϫ mice and controls. Hsd11b2Ϫ/Ϫ mice have a severe and progressive polyuric/polydipsic phenotype. In younger mice (ϳ2 mo of age), polyuria was associated with decreased abundance of aqp2 and aqp3 mRNA. The expression of other genes involved in water transport (aqp4, slc14a2, and slc12a2) was not changed. The kidney was structurally normal, and the concentrating response to water deprivation was intact. In older Hsd11b2 Ϫ/Ϫ mice (Ͼ6 mo), polyuria was associated with a severe atrophy of the renal medulla and downregulation of aqp2, aqp3, aqp4, slc14a2, and slc12a2. The concentrating response to water deprivation was impaired, and the natriuretic effect of the loop diuretic bumetanide was lost. In older Hsd11b2 Ϫ/Ϫ mice, the V2 receptor agonist desmopressin did not restore full urine concentrating capacity. We find that Hsd11b2 Ϫ/Ϫ mice develop nephrogenic diabetes insipidus. Gross changes to renal structure are observed, but these were probably secondary to sustained polyuria, rather than of developmental origin. polyuria; polydipsia; aldosterone; corticosterone; aquaporin-2; prenatal programming IN VITRO, ALDOSTERONE AND cortisol have equal affinities for mineralocorticoid receptors (MR) (3). In vivo, however, MR is selectively activated by aldosterone in target tissues such as the distal nephron (aldosterone-sensitive distal nephron; ASDN). This selectivity results from prereceptor metabolism of competing cortisol (corticosterone in rodents), which is an MR ligand, to cortisone (11-dehydrocorticosterone), which is not (16,21).In humans, congenital loss of 11␤ hydroxysteroid dehydrogenase type 2 (11␤HSD2) causes apparent mineralocorticoid excess (AME; OMIM 218030), presenting with hypertension, hypokalemic alkalosis, and a suppressed renin-angiotensinaldosterone system (38, 47). AME reflects activation of MR by glucocorticoids (47): with mineralocorticoid target proteins no longer subject to the homeostatic influence of the renin-angiotensin-aldosterone system, hypertension and electrolyte abnormalities develop secondary to renal salt and water retention. A similar profile is observed when AME is acquired following pharmacological inhibition of 11␤HSD2 (18). In rats, inhibition of 11␤HSD2 stimulates sodium reabsorption in the collecting duct following activation of the epithelial sodium channel (ENaC) (7).To better define the role of 11␤HSD2 in sodium a...

Comparative transcriptional profiling of renal cortex in rats with inherited stress-induced arterial hypertension and normotensive Wistar Albino Glaxo rats

“…In aldosterone target tissues, 11βHSD2 is coexpressed with mineralocorticoid receptors and protects the receptor from activation by glucocorticoids. It was found that decreased HSD11B2 activity is related to hypertension [ 21 ] and Hsd11b2 null mice are also hypertensive [ 22 ]. So, the increased Hsd11b2 transcription in ISIAH renal cortex may lead to decreased glucocorticoid action and be protective against excessive elevation of blood pressure.…”

Pressure natriuresis and the renal control of arterial blood pressure

“…The acute PN response has not been measured in Hsd11b2 ‐null mice but a chronic natriuresis develops as the disease progresses (Evans et al . ). This increased sodium excretion contracts ECFV but does not normalize BP and our data indicate that activation of the sympathetic nervous system may contribute both to the origins and maintenance of hypertension (Bailey et al .…”

Inherited secondary nephrogenic diabetes insipidus: concentrating on humans

“…A compelling argument for a causative role of the biochemical abnormalities is the observed complete reversibility of the sNDI with normalization of biochemistries after appropriate treatment. In this context, it is interesting to note the recent report of a urinary concentrating defect also in the mouse model of AME (Hsd11b2 Ϫ/Ϫ mice), which was indeed associated with a deficiency in Aqp2 mRNA (21). Curiously, the obvious experiment of confirming the reversibility of the urinary concentrating defect was not performed, despite the published clinical experience in humans.…”