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Original Studies |
Department of Nephrology and Hypertension (E.L., P.F., B.D., B.M.F., F.J.F.) and Kinderspital (K.J.), University of Berne, 3010 Berne, Switzerland; and Division of Endocrinology and Nephrology (U.S., A.M.S.), Universitätsklinikum Benjamin Franklin, Free University, Berlin 12200, Germany
Address correspondence and requests for reprints to: Paolo Ferrari, M.D., Department of Nephrology and Hypertension, University of Berne, Inselspital, 3010 Berne, Switzerland. E-mail: paolo.ferrari{at}insel.ch
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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THF) to cortisone (THE) metabolites by gas chromatography in
all the 37 SS subjects and in 37 age- and body habitus-matched SR
volunteers. Mean (THF+5THF)/THE ratio was markedly elevated in SS
subjects compared with SR subjects (1.51 ± 0.34
vs. 1.08 ± 0.26, P <
0.00001), indicating enhanced access of glucocorticoids to the
mineralocorticoid receptor in SS subjects. In 58% of SS subjects this
ratio was higher than the maximum levels in SR subjects. The
salt-induced elevation in arterial pressure increased with increasing
(THF+5THF)/THE ratio (r2 = 0.51,
P < 0.0001). A total of 12 alleles of the
polymorphic microsatellite marker were detected. Homozygosity for the
allele A7 was higher in SS subjects than in SR subjects (41
vs. 28%, P < 0.005), whereas the
occurrence of the allele A7 with allele A8 was lower in SS subjects
than in SR subjects (8 vs. 15%, P
< 0.03). The prevalence of salt sensitivity was 35% in subjects with
allele A7/A7, whereas salt sensitivity was present in only 9% of the
subjects with allele A7/A8. The (THF+5THF)/THE ratio was higher in
subjects homozygous for the A7 microsatellite allele as compared with
the corresponding control subjects. The prevalence of the
AluI allele was 8.0% in SR subjects and 5.4% in SS
subjects and did not correlate with blood pressure. The decreased
activity of the 11ßHSD2 in SS subjects indicates that this enzyme is
involved in salt-sensitive blood pressure response in humans. The
association of a polymorphic microsatellite marker of the gene with a
reduced 11ßHSD2 activity suggests that variants of the HSD11B2 gene
contribute to enhanced blood pressure response to salt in humans. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Patients with essential hypertension do not have overt signs of mineralocorticoid excess, however, more subtle changes such as a positive correlation between blood pressure and serum sodium levels or a negative correlation with potassium levels may suggest a corticosteroid influence (9). Recent studies have shown that the half-life of cortisol is significantly prolonged and the excretion of urinary cortisol metabolites increased in some patients with essential hypertension (10, 11). Moreover, a genetic association of a HSD11B2 flanking microsatellite and hypertension was also reported (12). In the "four-corner study," an impaired conversion of cortisol to inactive metabolites has also been reported in young men with higher blood pressure whose parents also had high blood pressure (13). Together, these studies suggest that the 11ßHSD2 enzyme may play a role in essential hypertension and in the sensitivity of blood pressure to dietary salt. A salt-sensitive (SS) response of blood pressure has not only been observed in patients with hypertension, but has also been well documented in young normotensive individuals (14). These subjects also display a number of traits, including increased pressor response to vasoactive substances, or mental stress, suppression of the renin-angiotensin system, and insulin resistance, features that can also be found in patients with essential hypertension (15). It has, therefore, been suggested that SS normotensive individuals may be genetically predisposed to the development of hypertension (16).
Thus, the main hypotheses addressed in this project were: 1) whether
the recently described AluI
[Glu178/Glu (G534A)] polymorphisms within (17)
or the polymorphic microsatellite marker flanking (GenBank AF071493)
(18) the HSD11B2 gene are related to salt-sensitivity in young
Caucasian normotensive subject; and 2) whether changes in blood
pressure due to salt-sensitivity are associated with changes in
11ßHSD2 activity as assessed by the urinary excretion ratio of the
cortisol (THF+5THF) to cortisone (THE) metabolites.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The 149 study subjects were unrelated young Caucasian male volunteers recruited among medical students from the Free University of Berlin. All subjects underwent routine clinical and laboratory evaluations to ensure that none had hypertension, hyperlipidemia, diabetes mellitus, or hepatic or renal disease. Only subjects with a blood pressure <140/85 mm Hg were included in the study. All participants gave their informed consent to participate in the study.
As described previously (19, 20), subjects were given a standardized low-salt diet containing 20 mmol sodium, 20 mmol chloride, 60 mmol potassium, and 20 mmol calcium per day for 7 days. Thereafter, the same diet with a daily supplement of 20 tablets of sodium (10 mmol NaCl per tablet; a gift of Ciba-Geigy, Horsham, UK) or placebo was administered in a randomized single-blind crossover fashion for 7 days, respectively. Throughout the dietary period, compliance was assessed by measuring the daily 24-h urinary sodium excretion by standard laboratory methods. At the end of each week, following a 30-min resting period, blood pressure was measured for assessment of salt sensitivity in the recumbent subject over 1 h at 5-min intervals with an automatic oscillometric device (DINAMAP 1846 SX; Critikon, Tampa, FL). As in previous studies (19, 20, 21), salt sensitivity was defined as a significant drop in mean arterial pressure >3 mm Hg under the low-salt diet calculated as the difference between the average of the 60 readings under the high- and low-salt periods (P < 0.05, paired t test for independent samples). The SEM for a single 60-min period ranged between 0.35 and 0.65 mm Hg. Salt sensitivity defined according to this protocol is a well-reproducible phenomenon in normotensive individuals (21).
PCR analysis
PCR amplification of exon 3 was carried out in a GeneAmp 9600 thermal cycler (Perkin Elmer Corp., Oak Brook, IL) as described previously (17). Primers were derived from the intronic sequences flanking exon 3 published elsewhere (4). PCR analysis of the polymorphic microsatellite marker (18) was performed by the automated fluorescent genotyping method using an unlabeled forward primer (5'-CCAGCCAGGTTGGAAGTGTG-3') and a fluorochrome-labeled reverse primer (5'-CAGTACGGTCTCCCCCATCT-3'). PCR reactions were performed by using 100 ng template DNA, 20 pmol of each primer, and 5 nmol of each dNTP in supplied PCR buffer with 2.5 U Ampli-Taq Gold (Perkin Elmer Corp.) in a total volume of 50 µl. Initial denaturation was at 95°C for 10 min, followed by 30 cycles of 95°C for 15 sec, 58°C for 15 sec, and 72°C for 45 sec. Final extension was at 72°C for 7 min.
Gel Analysis and sequencing
PCR products of exon 3 were analyzed on 12% acrylamide gels containing 7.25% glycerol using a two-buffer system, 4 µL of the PCR sample were loaded and DNA was visualized by silver staining (22). Sequence changes were detected by double band shifts on the gel. Identified variants were further analyzed by restriction digest of PCR products with the AluI enzyme cutter, according to standard methods.
The fluorescently labeled polymorphic marker fragments were analyzed using an ABI GENESCAN (Version 2.0.1 fc2) software on the Model ABI PRISM 377 (Version 1.1) automated sequencer (PE Applied Biosystems, Foster City, CA). Genotype data were generated using ABI GENOTYPER (Version 1.1r8) DNA fragment analysis software (PE Applied Biosystems).
Urinary steroid profile analysis
Urine samples were analyzed by gas chromatography according to the
method of Shackleton (23) [for the determination of tetrahydrocortisol
(THF), 5-tetrahydrocortisol (5THF), and tetrahydrocortisone
(THE)]. The analytical procedure consisted of hydrolysis, solid phase
extraction, derivatization, and purification of the samples by gel
filtration. A total of 2.5 mL urine mixed with 0.5 mL acetate buffer
0.5 M were hydrolyzed (for 3 h at 55°C) with
Sigma Chemical Co. (Buchs, Switzerland) Type I
powdered Helix promatia enzyme (12 mg) and 12.5 µL Boehringer
Mannheim (Ratkreuz, Switzerland) ß-glucuronide/aryl sulfatase
liquid enzyme. The resulting free steroids were extracted with a
Sep-Pak cartridge and taken to a final solution of 4 mL in methanol. To
this extract an internal standard mixture (5-androstane-3,
17-diol, stigmasterol, and cholesteryl butyrate, 2.5 µg each) was
added, and the sample was derivatized to form the
methyloxime-trimethylsilyl ether. Derivatization mixtures were purified
by gel filtration on Lipidex-5000 columns. Samples were analyzed on a
Carlo Erba (Milan, Italy) Gaschromatograph 2100 equipped with a
Merck and Co., Inc. (Darmstadt, Germany)
Hitachi D-2500 Chromato-Integrator. The derivatized
steroid samples were analyzed during a temperature-programmed run
(210–270°C) over a 40-min period. Several steroid mixtures
containing known amounts of all metabolites to be measured were
analyzed as calibration standards, and the values obtained in the urine
steroid analysis were determined relative to this calibration. In each
case, peak areas were quantified against the ones of androstane and
stigmasterol internal standards, and the mean values were taken as
final results.
Other biochemical variables
Plasma and urine potassium, sodium, and creatinine were measured by standard laboratory techniques. Plasma renin activity (PRA) and plasma aldosterone concentrations (PAC) were assayed by radioimmunoassay as previously described (24).
Statistics
Values are expressed as mean ± SD. Median values
and 95% confidence intervals (CIs) were used when appropriate.
Statistical differences between means were assessed by nonparametric
analysis, and the 2x2 contingency tables by 
2
test.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Age, height, and weight did not differ in SS subjects as compared with
SR subjects. In the two groups, the mean blood pressure was identical
on low-salt diet. When the diet was changed from a low to a high salt
intake, blood pressure increased in SS subjects and decreased slightly
in SR subjects (Table 1). The mean (±SD) values on a
high-salt diet were 116/61 ± 10/10 and 108/56 ± 7/7 mm Hg,
(P < 0.0001) in SS and SR subjects, respectively.
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Exon 3 of the HSD11B2 gene was amplified by PCR in all 149 subjects. Gel analysis of the PCR products revealed a total of 11 migration variants (7.4%). Migration variants were further analyzed after restriction digest with the AluI cutter demonstrating the presence of the AluI restriction polymorphism in all variants. All 11 subjects were heterozygous for the polymorphic marker. The AluI marker was positive in 2 of 37 SS subjects (5.4%) and 9 of 112 SR subjects (8.0%).
A total of 12 different alleles of the polymorphic microsatellite marker were detected among the 298 alleles analyzed. The length of PCR products varied from 356 nucleotides for allele A1 to 378 nucleotides for allele A12. Heterozygosity in this population reached 68%. Homozygosity for the allele A7 was higher in SS subjects than in SR subjects (41 vs. 28%, P < 0.005), whereas the occurrence of the allele A7 with allele A8 was lower in SS subjects than in SR subjects (8 vs. 15%, P < 0.03). The prevalence of salt sensitivity was 35% in subjects with allele A7/A7, whereas salt sensitivity was present in only 9% of the subjects with allele A7/A8.
Phenotyping
The mean (THF+5THF)/THE ratio in urines collected on low-salt
diet was markedly elevated in SS subjects as compared with SR subjects
(1.51 ± 0.34 vs. 1.08 ± 0.26, P
< 0.0001) (Fig. 1). Median values (and 95% CIs) for
these ratios were 1.56 (1.35–1.61) in SS subjects and 1.10
(0.92–1.15) in SR patients; in 58% of SS subjects the ratio was
higher than the maximum level observed in SR subjects. The urinary
(THF+5THF)/THE ratio was >1.5 in 21 SS subjects but only in 1 SR
subject, and in 8 SS patients this ratio was >1.8. The increased ratio
of (THF+5THF)/THE in SS subjects was due to a decreased production
of THE (3280 ± 1890 vs. 4530 ± 2380 µg/day,
P < 0.01), whereas THF+5THF [4840 ± 2670
vs. 4730 ± 2440 µg/day, P = not
significant (NS)] did not differ significantly in SS and SR
subjects in 24-hour urines. There was a positive correlation between
the salt-induced increase in mean arterial pressure and the urinary
ratio of (THF+5THF)/THE (r2 = 0.51,
P < 0.0001) (Fig. 2). Subjects with
the AluI polymorphic marker showed lower (THF+5THF)/THE
ratios than AluI-negative volunteers (1.05 ± 0.21
vs. 1.33 ± 0.38, P < 0.01). The
urinary ratio of (THF+5THF)/THE was significantly higher in subjects
with the A7/A7 microsatellite allele homozygosity (1.45 ± 0.29)
than in subjects with other alleles (1.24 ± 0.39,
P < 0.05) or with the allele pair A7/A8 (1.15 ±
0.25, P < 0.01).
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We analyzed the relationship between urinary steroid metabolites
and PRA, PAC, and potassium in the subjects whose urinary
(THF+5THF)/THE ratios were measured. PRA was significantly lower in
SS subjects as compared with SR patients (0.97 ± 0.79
vs. 1.12 ± 0.97 ng/mL/h, P < 0.05),
as was PAC (280 ± 20 vs. 370 ± 19 pmol/L,
P < 0.05), whereas plasma potassium did not differ
significantly in the two groups (4.2 ± 0.3 vs.
4.4 ± 0.3 mmol/L, P = NS) although there was a
tendency for lower potassium levels in SS subjects than in SR subjects.
PRA was positively associated with PAC (r2 =
0.57, P < 0.0001). There was a weak correlation
between urinary (THF+5THF)/THE ratio and PAC
(r2 = -0.23, P < 0.05) and a
tendency for a negative correlation between urinary (THF+5THF)/THE
ratio and PRA (r2 = -0.18, P =
NS).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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THF)/THE in young Caucasian SS
men. Moreover, allele analysis of a polymorphic microsatellite flanking
the HSD11B2 gene reveals a correlation with salt-induced blood pressure
elevation and impaired 11ßHSD2 activity, indicating that some
individuals with SS blood pressure have subtle genetic abnormalities of
the 11ßHSD2 enzyme, causing a decrease in renal cortisol inactivation
and an increased blood pressure susceptibility to salt.
The prevalence of salt sensitivity in this group was 25%, in
accordance with an approximate 30% frequency observed in the
normotensive white population (15). The activity of the 11ßHSD2 was
decreased in some, but not all, SS subjects (Fig. 1
). Although normal
values of the urinary (THF+5THF)/THE ratio for children are on
average 1.1 ± 0.3 (25, 26), for young adults these values range
from 0.6–1.3, with an average of 1.21 ± 0.06 (27). Moreover,
these values are 1.30 ± 0.07 in normal adult males and 1.15
± 0.11 in normal adult females (27). In 57% of SS subjects the
urinary (THF+5THF)/THE was >1.5 (1.52–2.47), whereas in the SR
group this ratio was <1.4 in all but three subjects, and none of them
had a ratio >1.65. Therefore, considering the urinary
(THF+5THF)/THE excretion ratio as an intermediate phenotype, it
seems that approximately half of the subjects with blood pressure
susceptibility to salt display a decreased 11ßHSD2 activity.
Our data are in apparent contrast with a recent observation that
subjects with highest urinary-free cortisol show the least sensitivity
of blood pressure to dietary sodium (28). There are two explanations
for this discrepancy. First, in the study by Litchfield et
al. (28) only urinary-free cortisol but not cortisone or
(THF+5THF)/THE ratio were measured, thereby not allowing a direct
evaluation of 11ßHSD2 activity; second, a reduced 11ßHSD2 activity
correlates with a decreased urinary excretion of free cortisone rather
than an increased urinary-free cortisol excretion (27). Thus, measuring
cortisone and its metabolites or (THF+5THF)/THE ratio in the urine
seems to be the most appropriate assay of renal 11ßHSD2 activity,
although it should be emphasized that the most specific test for
11ßHSD2 activity is provided by the metabolism of
11-[3H] cortisol, as described by Ulick
et al. (8).
There are two possible mechanisms for a reduced 11ßHSD2 activity. On one hand, it is possible that circulating factors may inhibit the renal 11ßHSD2 enzyme in the SS population (29). In a recent study, such inhibitors were described in some essential hypertensive patients (29). A low-salt diet increased these inhibitors in high/normal-renin but not in low-renin hypertensives (29). Considering that most investigators reported low levels of plasma renin in SS subjects (15), it seems unlikely that such factors play a key role in the reduced 11ßHSD2 activity of the SS subjects investigated. On the other hand, the presence of a genetic variant of the enzyme, with only slightly reduced activity, deserves consideration. This aspect has been recently predicted by the description of a young girl with low-renin hypertension but without the characteristic features of apparent mineralocorticoid excess (30). Analysis of the urinary excretion of steroid metabolites indicated a mild form of the syndrome, which was confirmed by genetic analysis. The identified mutant showed only a slightly reduced enzymatic activity in vitro (30). Based on this observation, we analyzed two known polymorphic markers of the HSD11B2 gene (17, 18) and their linkage to the intermediate phenotype of decreased 11ßHSD2 activity or the distant phenotype of salt-induced elevation in blood pressure.
The lack of correlation of the AluI (G534A) variant with either salt sensitivity or impaired 11ßHSD2 activity indicates that this polymorphism has no functional significance, at least in the heterozygous state. This observation is in line with the recently reported absence of a positive association between the AluI (G534A) marker and severe essential hypertension in sibships with multiple hypertensive sub-jects (18).
To analyze whether some Caucasian individuals with SS blood pressure may have more subtle genetic abnormalities of the 11ßHSD2 enzyme, responsible for an increased blood pressure susceptibility to salt, the microsatellite marker described by Brand et al. (18) was used. The analysis revealed a positive association with the allele A7 homozygosity and a negative correlation with allele pair A7/A8 of the microsatellite marker with salt sensitivity in this study suggest that the activity of the 11ßHSD2 enzyme may be genetically determined by variants in the HSD11B2 promoter or by the presence of undetected mutations in the HSD11B2 gene itself, an issue deserving further investigation.
The CA-repeat allele polymorphism was recently analyzed in a large
series of families with essential hypertension (18), and no correlation
was found between this marker and blood pressure in this group (18).
The apparent divergent findings of the latter investigation as compared
with the present study is explained by the lack of selection for the
blood pressure response to salt load in the patients studied by Brand
et al. (18). In fact, an association with the HSD11B2 locus
and essential hypertension was suggested by Watson et al.
(12) using a different microsatellite, which was shown to be
significantly linked to essential hypertension in blacks. Blacks are
more prone to develop low-renin hypertension, a form of salt-dependent
hypertension (15). Considering the relationship between genotype and
phenotype, in all subjects with the allele pair A7/A7 the
(THF+5THF)/THE ratio was higher than in the other patients. Even
though some subjects homozygous for the A7 allele were SR, a risk
remains that some individuals may develop a salt susceptibility later
in life. In fact, SR patients with this allele pair had, on average,
higher (THF+5THF)/THE ratios than the rest of the SR subjects.
In line with the findings in subjects with mutations in the HSD11B2
gene whose plasma renin and aldosterone levels are suppressed (4, 5, 30), we found lower PRA and PAC in the SS patients as compared with the
SR group, and these value tended to be inversely correlated with the
urinary (THF+5THF)/THE ratio. Thus, the relatively lower plasma
renin and aldosterone levels, along with the decreased 11ßHSD2
activity in SS patients, strongly suggest a role of this enzyme in the
salt-induced blood pressure increase in this population.
The present findings indicate that in some young normotensive white male subjects the blood pressure response to salt load is related to a genetically determined reduction in the activity of the enzyme 11ßHSD2. This might predispose to the development of hypertension with increasing age, along with excessive salt consumption. Biochemical analysis and targeted genotyping of the 11ßHSD2 enzyme may help to detect subjects at risk to develop hypertension or hypertensive patients, whose condition is mediated by renal sodium retention via this mechanism. This would help to tailor dietary salt restriction (31) and to chose antihypertensive drugs that modulate mineralocorticoid effects in selected patients.
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Acknowledgments |
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Footnotes |
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2 These authors contributed equally to this work.
Received June 3, 1999.
Revised July 20, 1999.
Accepted July 26, 1999.
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References |
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M. Quinkler, W. Oelkers, and S. Diederich In Vivo Measurement of Renal 11{beta}-Hydroxysteroid Dehydrogenase Type 2 Activity J. Clin. Endocrinol. Metab., December 1, 2000; 85(12): 4921a - 4922. [Full Text]
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J. A. Whitworth, G. J. Mangos, and J. J. Kelly Cushing, Cortisol, and Cardiovascular Disease Hypertension, November 1, 2000; 36(5): 912 - 916. [Abstract] [Full Text] [PDF]
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A. K. Agarwal, G. Giacchetti, G. Lavery, H. Nikkila, M. Palermo, M. Ricketts, C. McTernan, G. Bianchi, P. Manunta, P. Strazzullo, et al. CA-Repeat Polymorphism in Intron 1 of HSD11B2 : Effects on Gene Expression and Salt Sensitivity Hypertension, August 1, 2000; 36(2): 187 - 194. [Abstract] [Full Text] [PDF]
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MAP) and the urinary (THF+5