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Published in final edited form as: Hypertension. 2011 Jan 31;57(3):515–520. doi: 10.1161/HYPERTENSIONAHA.110.163782

Hsd11b2 HAPLOINSUFFICIENCY IN MICE CAUSES SALT-SENSITIVITY OF BLOOD PRESSURE

Matthew A Bailey 1,#, Eilidh Craigie 1,#, Dawn EW Livingstone 1, Yuri V Kotelevtsev 1,3, Emad AS Al-Dujaili 2, Christopher J Kenyon 1, John J Mullins 1
PMCID: PMC4830399  EMSID: EMS34331  PMID: 21282561

Abstract

Salt-sensitivity of blood pressure is an independent risk factor for cardiovascular morbidity. Mechanistically, abnormal mineralocorticoid action and sub-clinical renal impairment may blunt the natriuretic response to high sodium intake, causing blood pressure to rise. 11β-hydroxysteroid dehydrogenase type 2 controls ligand access to the mineralocorticoid receptor and ablation of the enzyme causes severe hypertension. Polymorphisms in HSD11B2 are associated with salt-sensitivity of blood pressure in normotensives. In this study, we used mice heterozygote for a null mutation in Hsd11b2 (Hsd11b2+/−) to define the mechanisms linking reduced enzyme activity to salt-sensitivity of blood pressure.

A high sodium diet caused a rapid and sustained increase in blood pressure in Hsd11b2+/− mice but not in wild-type littermates. During the adaptation to high sodium diet, heterozygotes displayed impaired sodium excretion, a transient positive sodium balance and hypokalemia. After 21 days of high sodium feeding, Hsd11b2+/− mice had an increased heart weight. Mineralocorticoid receptor antagonism partially prevented the increase in heart weight but not the increase in blood pressure. Glucocorticoid receptor antagonism prevented the rise in blood pressure. In Hsd11b2+/− mice, high sodium feeding caused suppression in aldosterone and a moderate but sustained increase in corticosterone.

This study demonstrates an inverse relationship between 11β-hydroxysteroid dehydrogenase type 2 activity, heart weight and blood pressure in a clinically important context. Reduced activity causes salt-sensitivity of blood pressure but this does not reflect illicit activation of mineralocorticoid receptors by glucocorticoids. Instead, we have identified a novel interaction between 11β-hydroxysteroid dehydrogenase type 2, dietary salt and circulating glucocorticoids.

Keywords: genetics, hypertension, renal, kidney, sodium

INTRODUCTION

Salt-sensitivity of blood pressure is an independent risk factor for cardiovascular mortality in normotensive individuals1 and an independent prognostic factor for essential hypertension2. The salt-induced increase in blood pressure reflects a complex interplay between renal, central and vascular systems. The mechanisms causing salt-sensitivity are not well defined but subclinical renal impairment and abnormal modulation of the reninangiotensin-aldosterone system (RAAS) by dietary salt may be contributory3. Even when aldosterone is low or normal, mineralocorticoid receptor (MR) blockade can be cardioprotective4 and pathophysiological activation of MR by alternative ligands has been found in rodent models of salt-sensitive hypertension5,6.

Cross-talk at the receptor level between the RAAS and hypothalamic-pituitary-adrenal (HPA) axis is prevented by 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2). This enzyme protects MR directly, by restricting the local availability of glucocorticoids7, and indirectly, by locking glucocorticoid-occupied MR in an inactive state8. Null mutations in the encoding gene, HSD11B2, cause Apparent Mineralocorticoid Excess (AME; OMIM +218030), which presents in children with salt-sensitive hypertension, hypokalaemia and low plasma aldosterone9. A type 2 variant of the disease (OMIM 207765) presents in adults10,11 as essential hypertension with mild abnormalities in steroid metabolism.

HSD11B2 is an attractive candidate gene for salt-sensitivity and polymorphisms associated with either blood pressure per se or salt-sensitivity of blood pressure have been found in several populations12-18. To define the role of the enzyme in the physiologic regulation of blood pressure, we previously generated mice with a targeted deletion of Hsd11b219,20. In the present study, heterozygote null mice (Hsd11b2+/−), which have only 50% of normal enzyme levels, were found to have salt-sensitive blood pressure and electrolyte abnormalities consistent with mineralocorticoid excess. However, we found no evidence for non-modulation of the RAAS and the increased blood pressure reflected activation of the glucocorticoid receptor (GR).

METHODS

Experiments were performed on heterozygote (Hsd11b2+/−) and wild-type (Hsd11b2+/+) male mice (aged 100-200 days) under a licence from the UK Home Office.

Studies in conscious mice

Blood pressure, measured by radiotelemetry, was recorded in mice initially maintained on standard chow (0.25% Na by weight) before high sodium feeding (2.5% Na by weight) over a 19-day period. Sodium balance was measured using metabolism cages. After acclimatization, baseline measurements were made over a 3-day period, after which mice were fed high sodium chow for a further 18 days. Water and food intake, urine and fecal output and mouse body weight was monitored daily. Mice were then decapitated and the kidneys taken for histological examination, measurement of 11βHSD2 activity and gene expression.

Measurements in anaesthetized mice

mice, fed either a control or high sodium diet for 4, 21 or 70 days, were anaesthetized (Inactin, 100mg/kg; IP) for measurement of mean arterial blood pressure (MBP) by direct cannulation. Evans Blue dye was injected IV for measurement of plasma volume and blood sampled for measurement of plasma potassium and osmolality. Urine was collected from the bladder for calculation of the urine sodium to potassium concentration ratio (UNa:K) and transtubular potassium gradient (TTKG).

Renal 11βHSD2 enzyme activity was assessed using thin layer chromatography (TLC) to measure the conversion of [3H]corticosterone to [3H]dehydrocorticosterone21. Kidney homogenates from Hsd11b2 null mice were used as negative controls and showed a conversion not significantly different from zero.

Inhibitor studies

mice received spironolactone, dexamethasone or RU38486 before and during high sodium feeding (please see http://hyper.ahajournals.org).

Quantitative PCR

Hsd11b2 mRNA was quantified by a validated Taqman assay. Data were normalized to wscr1 on a sample-to-sample basis. The expression of wscr1 was not different between genotypes and was not affected by high sodium diet.

Statistics

data are mean ± SE, except for cumulative sodium balance data, which are medians plus ranges. Comparisons were made using either unpaired t-test, ANOVA with Holm-Sidak post hoc test or the Kruskal-Wallis test, as appropriate.

RESULTS

Renal 11βHSD2 activity (Figure 1A) and Hsd11b2 mRNA levels in Hsd11b2+/− mice were ~50% that of Hsd11b2+/+ mice and not influenced by dietary sodium. In conscious Hsd11b2+/− and wild-type mice fed a control sodium diet, MBP and urinary sodium excretion were similar (Figure 1B & C). The UNa:K ratio tended to be lower in Hsd11b2+/− mice than in wild types (Hsd11b2+/−=0.39±0.07 vs Hsd11b2+/+=0.80±0.21; P=0.08) but sodium balance was neutral (Figure 1D).

Figure 1.

Figure 1

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The response to high sodium feeding in Hsd11b2+/+ (open bars/symbols) and Hsd11b2+/− (grey bars/symbols) mice, numbers (WT:HETS) in parentheses. A) renal 11β-hydroxysteroid dehydrogenase type 2 activity in mice fed a control or high sodium diet (n=6 in all); (B) 24h mean arterial blood pressure in conscious, unrestrained mice (n=4:6) with the transition from control to high sodium indicated by an arrow; C) 24h sodium excretion (n=7:10); D) 3-day cumulative sodium balances on control diet (basal) and during the adaptation to high sodium diet (n=7:10) and E) mean arterial blood pressure in anesthetized mice after 4d, 21d or 70d on high sodium diet (n=5:5 at each time point). Data are means ± SE or medians and ranges (panel D). *P<0.05, **P<0.01, ***P<0.001 compared to wild-type.

In Hsd11b2+/+ mice, high sodium feeding rapidly increased urinary sodium excretion without affecting either sodium balance or MBP. Hsd11b2+/− mice responded differently: the immediate natriuretic response was significantly blunted (Figure 1C) and the mice developed a positive sodium balance (Figure 1D). The UNa:K ratio increased immediately in both groups of mice in response to high sodium feeding but remained relatively suppressed in heterozygotes (Hsd11b2+/−=6.51±0.44 vs Hsd11b2+/+=8.46±0.69; P<0.05), indicating residual mineralocorticoid activity. MBP began to increase on the second day of high sodium feeding, reaching statistical significance at day 5, at which time neutral sodium balance had been restored.

Plasma volume, plasma potassium and MBP were measured in separate cohorts of mice after 4, 21 or 70 days of high sodium intake. On the control diet, Hsd11b2+/− and Hsd11b2+/+ mice had a similar plasma volume, plasma potassium and hematocrit values (Table 1). The TTKG was significantly higher in heterozygote mice (Hsd11b2+/− =13.7±0.9 vs Hsd11b2+/+=8.6±1.2; P<0.01). After four days of high sodium feeding, Hsd11b2+/− mice became hypokalemic and MBP was increased (Figure 1E). The TTKG was reduced but remained >7, indicating persistent potassium secretion in the collecting duct. The increased blood pressure in Hsd11b2+/− mice was not associated with volume expansion, plasma volume being lower (Hsd11b2+/−=1.48±0.07ml vs Hsd11b2+/+=2.13±0.02 ml; n=5 per group, P<0.01) and hematocrit higher (Table 1), than in Hsd11b2+/+ mice.

Table 1.

Plasma potassium (PK) and hematocrit in Hsd11b2+/− and Hsd11b2+/+ mice maintained on either a control (0.25% Na) or high sodium (2.5% Na) for either 4, 21 or 70 days. Data are mean ± SE with number of mice in parentheses.

Diet PK (mmol/l) Hematocrit
Hsd11b2+/− Hsd11b2+/+ Hsd11b2+/− Hsd11b2+/+
Control 4.55 ± 0.14
(8) 		4.25 ± 0.08
(8) 		0.43 ± 0.07
(8) 		0.42 ± 0.1
(8)
High Na
4 days		 3.74 ± 0.10*
(5) 		4.14 ± 0.12
(6) 		0.46 ± 0.05†
(5) 		0.41 ± 0.08
(6)
High Na
21 days		 3.72 ± 0.11†
(7) 		4.83 ± 0.34
(9) 		0.42 ± 0.07
(7) 		0.42 ± 0.07
(9)
High Na
70 days		 3.40 ± 0.21†
(6) 		4.45 ± 0.29
(5) 		0.43 ± 0.07
(6) 		0.42 ± 0.03
(5)
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Statistical comparisons were made using t-test

*

P<0.05,

†

P<0.01.

After 21 days on high sodium diet, Hsd11b2+/− mice remained hypokalemic but hematocrit had normalized (Table 1). In heterozygote mice, high sodium feeding significantly increased heart and kidney weight (Table 2) but significant albuminuria was not detected over the 21-day experiment. Consistent with this, the kidneys of salt-fed heterozygote mice appeared normal under histological examination. After 70 days of salt loading, the MBP differential between genotypes had increased to ~20mmHg (Figure 1E) but hematocrit remained normal (Table 1).

Table 2.

Body, heart and kidney wet weight at sacrifice in Hsd11b2 heterozygote mice maintained for 21 days on either a control (0.25% Na) or high sodium (2.5% Na) diet. Mice were sham-operated or had slow-release pellets containing spironolactone (SPIRO) or RU38486 implanted subcutaneously. Data are mean ± SE with number of mice in parentheses. Statistical comparisons were made using one-way ANOVA, with P value shown in the final column.

Parameter Control diet High sodium High sodium + SPIRO High sodium + RU38486 ANOVA P
n 8 9 10 8
Body weight (g) 32.7±1.2 33.9±1.0 32.6±0.5 33.1±0.7 NS
Heart weight (mg) 129.8±3.9 162.5±6.0† 141.5±5.9 144.3±2.7 <0.01
Kidney weight (g) 325.8±12.7 393.6±21.8* 350.4±8.0 368.6±11.9 <0.05
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Bonferroni post-tests

*

P<0.01,

†

P<0.001 versus control.

Plasma aldosterone (Figure 2A) and 24-hour urinary aldosterone excretion (Figure 2B) were lower in Hsd11b2+/− mice on a control sodium diet, indicating tonic suppression of the RAAS. Adaptation to high sodium feeding caused an appropriate reduction in aldosterone in both genotypes: aldosterone remained significantly lower in heterozygotes (Figure 2A and B). Plasma corticosterone was comparable between genotypes on a control sodium diet but was elevated in Hsd11b2+/− mice following high sodium feeding (Figure 2C). Plasma samples were collected under terminal anesthesia but we do not attribute the increased levels observed in heterozygotes to this, since 24 hour urinary corticosterone excretion (a surrogate for plasma corticosterone22) obtained in conscious, unrestrained mice was also elevated in Hsd11b2+/− mice by dietary sodium loading (Figure 2D). Deoxycorticosterone excretion was not different between genotype and was not affected by dietary sodium (data not shown).

Figure 2.

Figure 2

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Steroid profiles in Hsd11b2+/− (grey bars) and Hsd11b2+/+ mice (open bars), with numbers (WT:HET) given in parentheses. A) Plasma aldosterone measured in terminal arterial blood samples after 21 days on either control or high sodium diet (n=8 for all); B) 24h urinary aldosterone excretion in mice on control sodium diet and during the adaptive and plateau phases following high sodium feeding. (n=10:7); C) Plasma corticosterone in terminal arterial blood samples, as before; D) urinary corticosterone excretion, as before. Data are means ± SE. *P<0.05, **P<0.01 compared to wild-type. Within genotype comparisons are as stated.

To identify mechanisms underlying salt-sensitivity in Hsd11b2+/− mice, we first used dexamethasone to suppress the HPA axis20, reducing 7am plasma corticosterone to ~20nmol/l in both groups. Dexamethasone abolished the sodium-induced differential between genotypes for both blood pressure (Hsd11b2+/−=96.8±1.8mmHg vs Hsd11b2+/+=94.5±0.9mmHg; NS) and plasma potassium (Hsd11b2+/−=5.70±0.12mM vs Hsd11b2+/+=5.83±0.38mM; NS). One interpretation of these data would be to attribute salt-sensitivity in heterozygotes to spill-over activation of MR by glucocorticoids. In fact, the normalization of blood pressure between genotypes was attributable to a significant (P<0.05) dexamethasone-induced pressor response in wild-type mice, which was not observed in heterozygotes. Spironolactone was therefore administered to assess the involvement of MR in the salt-sensitive phenotype. MR blockade did not prevent the salt-induced increase in blood pressure observed in Hsd11b2+/− mice, which remained ~10mmHg higher than in Hsd11b2+/+ mice (Figure 3A). Similarly, spironolactone did not prevent heterozygote mice becoming hypokalaemic during high sodium feeding (Figure 3B). During MR blockade, the UNa:K ratio remained lower (Hsd11b2+/− = 0.94±0.60 vs Hsd11b2+/+ = 2.43±1.80; n=7/5, P=0.06). Despite the lack of effect on blood pressure, spironolactone partially prevented the salt-induced increase in heart weight observed in Hsd11b2+/− mice (P<0.05, Table 2).

Figure 3.

Figure 3

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A) mean arterial blood pressure and B) plasma potassium in Hsd11b2+/+ (open bars) and Hsd11b2+/− (grey bars) mice maintained for 21 days on a control (n=8:8) or high sodium (n=7:9) sodium diet. In separate groups, the mineralocorticoid receptor antagonist spironolactone (SPIRO, n=8:7) was administered before and during high sodium feeding. *P<0.05, **P<0.01. ***P<0.001, compared to wild-type mice.

The GR antagonist RU38486 prevented the sodium-induced increase in blood pressure (Figure 4A) and partially prevented the increased in heart weight (Table 2) observed in the heterozygotes. RU38486 also normalized plasma potassium (Figure 4B) and the UNa:K ratio.

Figure 4.

Figure 4

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A) mean arterial blood pressure and B) plasma potassium in Hsd11b2+/+ (open bars) and Hsd11b2+/− (grey bars) mice maintained for 21 days on high sodium diet. Mice received the glucocorticoid receptor antagonist, RU38486 (n=9:8) or vehicle (n=8:6) before and during high sodium feeding. *P<0.05, ***P<0.001. Within genotype comparisons as stated.

DISCUSSION

Deficiency in 11βHSD2 promotes salt-retention, potassium wasting and hypertension, thought to reflect unregulated activation of renal MR by glucocorticoids9,23. AME arises in children who are homozygous9 or compound heterozygous24 for mutations that ablate 11βHSD2 activity. AME is rare and the majority of those carrying a single mutated allele appear normal9. Detailed long-term follow up of heterozygotes is lacking but evidence suggests abnormal steroid excretion and a propensity toward low-renin hypertension in later life9,25. A variant of AME associated with reduced enzyme velocity causes hypertension in older individuals10,11 and an age-dependent decline in 11βHSD2 activity has been reported26. Defects in 11βHSD2 may therefore be a risk factor for hypertension in the general population.

In the present study we identified a strong sensitivity of blood pressure to dietary sodium intake in mice heterozygote for a null mutation in Hsd11b2. On a control diet, heterozygote mice displayed subtle signs of mineralocorticoid excess but had no derangements in blood pressure or plasma electrolytes and were in neutral sodium balance. The transition to high salt feeding uncovered in heterozygote mice a blunted renal natriuretic response: transient sodium retention preceded a rise in blood pressure by 24-48 hours. Hsd11b2+/− mice also developed hypokalemia. The suppressed UNa:K ratio and TTKG >7, suggested enhanced mineralocorticoid bioactivity in the distal nephron. The RAAS appeared to be appropriately modulated by dietary salt: overt aldosterone excess does not cause the sodium retention in Hsd11b2+/− mice.

In mice20 and humans9 lacking 11βHSD2, glucocorticoids have been shown to act as unregulated mineralocorticoids. In the current study sodium loading did not affect 11βHSD2 activity, consistent with previous reports27. Further diminution of the enzymatic barrier does not contribute to salt-sensitivity in heterozygote mice but spillover activation of MR following an increase in circulating corticosteroid was indicated. However, spironolactone (administered at a dose shown to be effective against high concentrations of glucocorticoid5) did not alleviate the symptoms of mineralocorticoid excess in salt-loaded heterozygote mice and we therefore suggest that inappropriate activation of MR is not causal. Our study does, however, suggest a cardioprotective role for MR4, independent of blood pressure since spironolactone partially rescued the salt-induced increase in heart-to-body weight ratio in Hsd11b2+/− mice.

At present we cannot define the mechanisms leading to increased corticosterone. However, salt-sensitive individuals display an attenuated glucocorticoid clearance28 and glucocorticoid regeneration by renal 11βHSD1 has been linked to salt-sensitivity in rats29. In the present study, impaired peripheral metabolism alone cannot account for the rise in plasma corticosterone since 11βHSD2 was not regulated by salt intake. It is possible that the HPA axis is activated during the transition to high sodium diet as has been reported in salt-sensitive humans30.

Mechanistically, the alterations in UNa:K and TTKG provide compelling evidence that ENaC activation in the ASDN underpins the sodium retention in Hsd11b2+/− mice. GR blockade prevented the development of the salt-induced phenotype, and this is consistent with regulation by GR of serum glucocorticoid regulated kinase 1 and ENaC5,31. Moreover, recent studies indicate that 11βHSD2 regulates the translocation of GR into the principal cell nucleus32, thereby governing transcriptional responses to glucocorticoids.

Surprisingly, sodium retention was associated with volume contraction, rather than expansion. This may reflect a countervailing influence of GR on vascular permeability and compliance. Redistribution of fluid out of the vascular space is characteristic of glucocorticoid excess and we have previously noted plasma volume contraction in other relevant models5,19. The absence of volume expansion in Hsd11b2+/− mice challenges the assumption that the salt-sensitive phenotype is an uncomplicated renal phenomenon. 11βHSD2 is expressed in other sites critical to blood pressure homeostasis and alternative explanations for the salt-sensitivity should be considered. For example, moderate glucocorticoid excess inhibits eNOS expression by the vascular endothelium33,34, an effect normally buffered by 11βHSD234. Suppression of 11βHSD2 exacerbates the inhibition34, which could contribute to the GR-driven increase in blood pressure observed here. Similarly, central inhibition of 11βHSD2 exerts a strong pressor effect35. Hypertension in the Hsd11b2−/− is maintained by catecholamine action19 and a contribution of the sympathetic nervous system to the salt-sensitivity in heterozygotes cannot be excluded.

Perspective

Genetic, acquired or age-dependent reductions in 11βHSD2 may adversely affect blood pressure homeostasis. Our study demonstrates an inverse relationship between 11βHSD2 and blood pressure in a clinically important context: high sodium intake36 and salt-sensitivity of blood pressure1,2 are important risk factors for cardiovascular death. Our data suggest that MR activation does not cause the salt-sensitivity of blood pressure but contributes to the cardiac hypertrophy. We have identified a potential role for 11βHSD2 in governing GR access and speculate that this may involve activation of HPA axis.

Supplementary Material

1

ACKNOWLEDGEMENTS

We thank Gillian Brooker and Ali Ashek for surgical assistance, Nina Kotelevtseva for genotyping and Forbes Howie for albumin measurements.

FUNDING SOURCES This work was funded in part by Wellcome Trust Principal (JJM) and Intermediate (MAB) Fellowships, a Medical Research Council Capacity Building PhD studentship (EC) and was supported by a British Heart Foundation Centre of Research Excellence (CoRE) award.

Footnotes

DISCLOSURES None

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