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Original Studies |
Clinical Biochemistry, Royal Infirmary (M.P.), Edinburgh; Medical Research Council Blood Pressure Group, Western Infirmary (C.D.H., R.F., J.M.C.C., M.C.I., N.H.A.), Glasgow; and Molecular Medicine Centre, Western General Hospital (C.J.K.), Edinburgh, Scotland
Address all correspondence and requests for reprints to: Christopher J. Kenyon, Molecular Medicine Center, Western General Hospital, Edinburgh, EH4 2XU, United Kingdom. E-mail: cjk{at}srv0.med.ed.ac.uk
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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5ß-reductase activity (allo-THF/THF + THE) appeared lower in AA than
aa subjects (0.22 ± 0.04 cf. 0.33 ± 0.06;
P < 0.005) but were not judged to be significantly
different when corrected for multiple comparisons. Single and
multivariate analyses were carried out to determine which variables
influence GR binding characteristics and glucocorticoid responsiveness
and to see whether cardiovascular risk factors (blood pressure and body
fat) were influenced by glucocorticoid-dependent functions. Only
15–20% of the variations in the dissociation constant
(Kd) and maximum binding capacity (Bmax) were
influenced by other variables; plasma cholesterol was the most
important for affinity and plasma sodium concentration for binding
capacity. Multivariate analysis showed that several factors including
GR genotype and urinary cortisol account for 10% of the variation of
in vivo responses to glucocorticoid hormones; plasma
calcium concentration was the only variable that contributed to
in vitro sensitivity of leukocytes to
dexamethasone. Glucocorticoid-dependent responses were of negligible
importance in determining blood pressure or percentage body fat within
the narrow physiological ranges of the present study. We conclude that
GR genotype affects steroid sensitivity in a tissue-specific manner
because of altered GR function or possibly because of linkage to a
locus that controls hormone access to the receptor by influencing
steroid metabolism. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We characterized phenotype in subjects of known GR genotype by assessing binding of dexamethasone in mononuclear leukocytes and by measuring glucocorticoid responsiveness in the same population of cells. In addition to these in vitro tests, we examined the relationship between genotype and in vivo vascular response to glucocorticoids as the degree of blanching following overnight, direct exposure of discrete areas of skin to hormone (8).
Endogenous glucocorticoids such as cortisol could increase blood pressure via glucocorticoid (type 2) or mineralocorticoid (type 1) receptors (9). Indeed, it is thought that the hypertension and hypokalemia that are associated with mutations of GR are because of excess mineralocorticoid activity (10, 11). In these patients, plasma cortisol, which is raised because of impaired GR, binds to type 1 mineralocorticoid receptor (MR). Accordingly, in the present study, we have assessed separately variables that conventionally are regarded as mineralocorticoid receptor-dependent (plasma renin, plasma aldosterone, hematocrit, and urinary Na/K) or GR-dependent functions (white blood cell number, plasma cortisol, and lipid metabolism).
Finally, we took into account recent hypotheses suggesting that corticosteroid hormone action is modulated by steroid metabolizing enzymes that govern access to receptors (12, 13) and enhance (14, 15) as well as inhibit activity. Urinary steroid metabolite ratios have been measured to give an indication of enzyme activities.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Sixty-four normotensive Caucasian male subjects age 18–40 yr were studied. A careful family history was obtained with particular attention to hypertension, diabetes mellitus, and cardiovascular disease. All subjects provided written informed consent. The study was approved by the Ethical Committee of the Western Infirmary Trust.
Study design
Urine was collected for 24 h before the tests. All subjects arrived at 0830 h. The mean of two blood pressure measurements was recorded after 30 min recumbency and again after 5 min in an upright position, using a Hawksley random zero sphygmomanometer. Body mass index (BMI) was calculated as weight/height2. Measurements of skinfold thickness (16) were used to estimate body density after normalizing for age-dependent variations; these data are presented as percentage body fat. Blood for biochemical tests was withdrawn from an antecubital vein after the subjects had been recumbent for at least 30 min. On a separate occasion, volunteers arrived between 1500 and 1700 h and again at 0830 h on the following day for a skin vasoconstriction test.
Skin blanching
Various amounts (0, 4.9, 19.5, 78.1, 313, 1250, and 5000 ng in 5 µL ethanol) of budesonide (Astra, Kings Langley, UK) were applied in duplicate, in random order, to discrete areas (49 mm2 separated by silicone grease) of the flexor surface of the forearm as described by Teelucksingh et al. (17). After drying, the area was covered with polyester film for 18 h. The degree of blanching was assessed on a scale of 0–3 by a blind independent observer. For each volunteer, a response curve was plotted and an EC50 value for budesonide calculated.
Leukocyte studies
As previously described (18), mononuclear leukocytes prepared from 50 mL citrated blood were used to measure both GR binding characteristics and dexamethasone-sensitive lysozyme release. Dissociation constants (Kd) and binding capacity (sites/cell) for dexamethasone were calculated using the curve-fitting program Ligand (19).
Lysozyme activity in the supernatant was measured photometrically as lysis of Micrococcus lysodeikticus using human recombinant lysozyme as a standard. An IC50 value for dexamethasone was calculated for each individual.
Genotyping of GR
Total genomic DNA was extracted from white blood cells as described (20). Approximately 10 µg was digested using the restriction enzyme BclI (3, 21). Restriction fragments were separated by electrophoresis on 0.8% agarose gel and transferred onto Hybond-N nylon membrane (Amersham, Buckinghamshire, UK) by Southern blotting (4). Fragments were identified as either A [4.5 kilobases (kb)] or a (2.8 kb) by hybridizing the membranes using a 32P-labeled 4.3-kb human GR complementary DNA (22) in 7% SDS/0.5 M phosphate buffer (pH 7.0) at 65 C overnight. Nonspecific binding was washed off in 2x standard saline citrate in 0.1% SDS at 65 C. The membranes were exposed to Hyperfilm MP (Amersham), with intensifying screens, for at least 3 days at 70 C.
Biochemical investigations
Routine biochemical and hematological measurements (electrolytes, cholesterol, creatinine, hematocrit, and differential blood cell counts) were carried using autoanalyzers. Aldosterone and cortisol in plasma and urine were measured by standard RIA (Diagnostic Products, Los Angeles, CA). Plasma renin concentration was measured by RIA of generated angiotensin I (AI) (23). Urinary steroid metabolites were analyzed by gas chromatography-mass spectrometry as described previously (24).
Statistical analyses
The summary statistics are presented throughout as means and SE. For each individual variable, mean measurements for each genotype were compared by a one-way ANOVA. The significance level for the four variables of primary interest [receptor Kd and maximum binding capacity (Bmax) for dexamethasone, IC50 of lysozyme release by dexamethasone and skin vasoconstriction by budesonide] was set at P < 0.05, and that for 24 secondary variables at P < 0.0021 (Bonferroni correction for multiple comparisons). Variables with positively skewed distributions were analyzed on a logarithmic scale. Subsequently, pairwise differences were examined by Bonferroni corrected two sample t tests. Simple and multiple linear regression was used to investigate the factors influencing glucocorticoid binding characteristics, glucocorticoid responsiveness, mineralocorticoid-dependent variables, and cardiovascular risk factors with important covariates being selected stepwise for multivariate models.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Restriction fragment length polymorphism analysis identified 6
subjects homozygous for the A allele, 7 homozygous for the a allele,
and 51 heterozygotes. There were no significant differences between
these genetic groups in terms of age, blood pressure, BMI, and
percentage of body fat (Table 1
).
Leukocytes from AA subjects tended to have higher Kd values
for dexamethasone (7.7 ± 1.5, 6.0 ± 0.4, 5.9 ± 0.8
for AA, Aa, and aa subjects, respectively) and lower sensitivity for
inhibitory effects of dexamethasone (Fig. 1B) than those from aa subjects (and
intermediate values for the Aa group), but these differences did not
achieve statistical significance. The number of dexamethasone binding
sites/cell (Bmax) did not differ between genotypes (AA:
6050 ± 750; Aa: 5540 ± 230; aa: 5100 ± 750). AA
subjects were significantly more sensitive (P = 0.012,
log transformed data) than aa subjects to topical budesonide; the Aa
group had an intermediate EC50 value (Fig. 1A).
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). Plasma renin concentration was
also similar in the three groups (AA: 38.7 ± 11.7; Aa: 29.7
± 2.3; aa: 34.1 ± 7.1 ng AI/mL-1/h-1).
Plasma and urine corticosteroid concentrations are summarized in Table 3. There were no significant differences
between groups, although plasma and urinary cortisol values tended to
be higher in AA subjects than in aa subjects. The ratio of
tetrahydrocortisol (THF) + allo-THF to tetrahydrocortisone (THE), an
index of 11ß-hydroxysteroid dehydrogenase (11ß-HSD) activity, was
not significantly different between groups (Fig. 2A). The ratio of allo-THF to THF + THE
(Fig. 2B) appeared higher in aa subjects than in AA subjects, with an
intermediate value for heterozygotes (P = 0.027). This
is suggestive of increased 5-reductase (or lower 5ß-reductase)
activity in the aa group. However, the P value for a
comparison between AA and aa groups was 0.005, which did not meet the
criteria of significance (P < 0.0021) when corrected
for multiple comparisons of secondary variables.
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Single and multiple regression analyses were carried out to determine which variables influenced, first, GR binding characteristics of dexamethasone in leukocytes (Kd and Bmax) and, second, responsiveness to glucocorticoids in vitro (dexamethasone-induced inhibition of lysozyme release) and in vivo (budesonide-induced skin blanching). We also considered whether various indices of glucocorticoid function influenced variables that are regarded as mineralocorticoid-dependent variables (urinary Na/K ratio and plasma renin activity) or cardiovascular risk factors (percent body fat and mean blood pressure).
Single variate analysis showed that loge (Kd)
values for dexamethasone and plasma cholesterol values correlated with
each other (P < 0.05; Fig. 3A). In designing a multivariate model to
consider whether other variables might influence Kd and
Bmax values in the present study, we selected those which,
from a table of correlation values, appeared most probable to have
causative effects. By single variate analysis, loge
(Kd) values correlated weakly (not significantly) with
plasma triglycerides (negative), GR genotype, plasma and urinary
cortisol, and urinary cortisol metabolites. When these factors were
subjected to multivariate analysis, 20% of loge
(Kd) variation was accounted for by a model that included
plasma cholesterol, Bmax, and the 5/ß ratio of reduced
cortisol metabolites (P = 0.002). Similarly, the model
that accounted for the biggest proportion of the variation in
Bmax (16%) included just two variables, Kd and
plasma Na+ (P < 0.01); plasma
Na+ correlated with Bmax when considered in
single variate analysis (Fig. 3B).
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Budesonide-sensitive skin blanching (in vivo responsiveness to glucocorticoids) correlated with only one variable, urinary cortisol (P < 0.05; single variate analysis). Urinary cortisol and GR genotype accounted for approximately 10% of variation in skin sensitivity in a multivariate model (P = 0.031).
By single variate analysis, GR binding characteristics did not seem important determinants of mineralocorticoid activity. In multivariate analysis, a model that included urinary aldosterone and allo-THF and plasma sodium concentration accounted for 28% of the variation in urinary Na/K ratio (P < 0.0005). Plasma renin levels were bimodally distributed, with a clear subgroup of patients with values >40 ng AI/mL/h. When high and low renin groups were compared, there were no significant differences in any of the glucocorticoid-dependent variables. Separate regression analysis of high (n = 13) and low renin groups (n = 45) showed that white blood cell number correlated significantly with high renin values (P = 0.033).
Two cardiovascular risk factors, blood pressure and body fat, were analyzed in some detail. Using multivariate analysis, a model that included percentage body fat and the ratio of urinary reduced cortisol metabolites accounted for 22% of variation in mean blood pressure (P = 0.001). Three principal factors contributed 29% to variation in percentage body fat: age, sodium excretion, and glomerular filtration rate (P < 0.0005).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The restriction site for BclI that gives rise to the GR polymorphism lies out with the exonic region of the gene and conceivably might affect the GR gene promoter. Differences in the GR promoter could give rise to differences in receptor expression levels. By selectively affecting either repressor or enhancer sites within the promoter, glucocorticoid sensitivity will be increased or decreased, respectively, possibly in a tissue-specific manner. Differential usage of the promoter would explain why the skin sensitivity to budesonide of our AA subjects was enhanced compared with aa subjects, whereas white blood cell lysozyme release tended to be less sensitive to dexamethasone, and circulating cortisol concentrations were unaffected. However, mechanisms controlling the human GR promoter usage are yet to be elucidated (25).
An alternative explanation, again based on differential expression,
could result from the two isoforms of GR that have recently been
described (26, 27). The ß-isoform does not bind ligand itself but can
competitively inhibit ligand effects mediated through the -isoform.
Because it has been suggested that and ß are present in varying
amounts in different tissues, this represents an alternative way of
controlling tissue sensitivity that potentially could be influenced by
GR polymorphism.
The molecular basis of glucocorticoid resistance is underinvestigated (for reviews see Ref.28). The idea of differential tissue sensitivity is to be anticipated from earlier studies (29, 30, 31). These earlier studies also described sexual dimorphism in the phenotype of glucocorticoid resistance which is why the present study was restricted to one sex. In part phenotypic, differences can be explained by an imbalance of steroid hormones leading to inappropriate activation of transcription factors (see below). More recently the importance and complexity of interactions of GR with other proteins has been appreciated (32). In the case of some patients with steroid-resistant asthma, for example, it is suggested that GR interaction with inappropriately high levels of the activating protein-1 transcription factor in peripheral mononuclear cells prevent GR from reacting with response elements on DNA (33). Glucocorticoid treatment of patients with tissue-specific resistance causes excess glucocorticoid activity at those other sites that respond normally.
GR interaction with proteins, whether other transcription factors or secondary corepressors and coactivators, often involves GR regions separate from the ligand binding domain (32, 34, 35, 36). As was recently shown (37), mutations at sites on the GR molecule that are important for protein-protein interactions may affect transactivation properties of GR in a tissue-specific manner depending on which gene pathway is involved. If such a mechanism were to be implicated in the present study, one would have to argue that the GR polymorphism marked a mutation of an additional site on an expressed region of the GR gene or of a non-GR protein that interfered with the process of GR-mediated transactivation.
Specificity of steroid hormone action can also be determined by
steroid-metabolizing enzymes, which modulate hormone access to
receptors. The principal enzymes involved, 11ß-HSD and 5- and
5ß-reductases (12, 13, 38, 39, 40, 41), are expressed in a tissue-specific
manner. Skin contains several steroid-metabolizing enzymes, and
glucocorticoid effects are potentiated by enzyme inhibitors such as
carbenoxolone (17). In contrast, leukocytes do not metabolize cortisol,
and cortisol binding is unaffected by enzyme inhibitors. In the present
study, budesonide and dexamethasone (poor substrates for metabolism)
were tested, which makes it unlikely that steroid metabolism could
directly account for variations of in vivo and in
vitro sensitivity to glucocorticoids. However, if metabolism
governs hormone action, this might, secondarily, modulate GR action,
which would then be revealed by tests with synthetic steroids. The
effect of altered metabolism and secondary changes of gene expression
may be of little net importance for endogenous hormone action.
Nevertheless, this analysis agrees with our observations that 5- and
5ß-reduced cortisol metabolites tend to differ between genotypes, and
supports previous observations of a relationship between the reduced
metabolites of cortisol and blood pressure (24). Against this
hypothesis is evidence that 11ß-HSD rather than 5- and
5ß-reductases regulates skin sensitivity to cortisol. Moreover,
urinary steroid metabolites may not necessarily reflect metabolism in
skin or any other target tissue. GR genotype could be in close linkage
dysequilibrium with a separate marker of cardiovascular disease. This
is compatible with our findings that some but not all GR-dependent
variables are affected. Thus, altered skin sensitivity could be an
intrinsic property of vascular smooth muscle and altered steroid
metabolism may not be correlated with skin vasoconstriction (42).
However, if GR polymorphism is a function of some fundamental aspect of
vascular function, one must question why other variables, more commonly
associated with vascular reactivity (renin and blood pressure) were
unaffected. On balance, therefore, considering that the polymorphism
has been positively identified with a GR locus and because, of the many
variables tested, the two that were most markedly affected by the
polymorphism were associated with glucocorticoid action or metabolism,
we suggest that GR function is affected by genotype.
Our primary aim was to define the phenotype of a GR polymorphism, but we also observed variations in GR binding characteristics that were greater than anticipated from our previous estimates of the interassay variation (18). This observation raised two questions. First, are Kd and Bmax values influenced by any of the other measured variables? Second, do variations in binding characteristics affect responsiveness to glucocorticoids and/or indices of mineralocorticoid activity? Single and multivariate regression analyses were used to try to answer these questions.
For Kd and Bmax values, small percentages of variation could be accounted for by other variables. Plasma cholesterol, Bmax, and GR genotype were implicated in a multivariate model of Kd variation, but only plasma cholesterol was significant when analyzed alone. Plasma cholesterol could affect steroid uptake by cells but, because glucocorticoids are known to increase plasma cholesterol, it is more likely that variations of Kd cause differences in plasma cholesterol and the other variables.
Variations of Bmax, even by single variate analysis, are associated with differences in plasma sodium. It is difficult to imagine how sodium might affect Bmax, and again it is more likely that Bmax, by influencing glucocorticoid activity, alters membrane cation transport and hence electrolyte homeostasis. In a multivariate model, Kd was the only other variable that influenced Bmax but, because the derivation of Kd and Bmax are interdependent, this may not be of significance. Neither dexamethasone-induced lysozyme release from leukocytes nor budesonide-induced skin vasoconstriction were strongly influenced by glucocorticoid receptor characteristics. Bmax, Kd, GR genotype, and plasma cortisol concentration were contributory factors in a model that accounted for 17% of leukocyte sensitivity
Renal mineralocorticoid receptors are normally protected from endogenous glucocorticoid hormones by 11ß-HSD (12, 13), but hypertension can arise if plasma cortisol overwhelms this protective mechanism (11, 43, 44). For example, mutations in GR causing glucocorticoid resistance and impaired feedback control lead to increased plasma cortisol and symptoms of mineralocorticoid excess. Despite marked variation in GR binding characteristics, neither Kd nor Bmax appeared to primarily affect either of two classical indexes of mineralocorticoid activity, suppression of plasma renin activity and decreased urinary Na/K ratios. Plasma cortisol concentrations did correlate with urinary Na/K ratios, but because plasma aldosterone concentration did too, this may reflect dual control of aldosterone and cortisol secretion.
Finally, although urinary cortisol metabolites, GR genotype, Kd, and plasma cortisol concentrations did feature as minor factors in blood pressure and percent body fat determination, we have not established that glucocorticoid hormones are involved in the development of obesity or hypertension (4, 5). Our subjects were normal volunteers without the extremes of blood pressure or BMI that were the criteria used to select patients in previous clinical studies (45, 46).
In summary, glucocorticoid-dependent vasoconstriction is affected by GR
polymorphism. These data are compatible with the observation that
individuals with the AA genotype are predisposed to develop
hypertension or obesity. We suggest that the polymorphism does not
affect the receptor affinity but may lead to tissue-specific
differences in GR expression by affecting the GR promoter region.
Steroid metabolism by 5- and 5ß-reductase enzymes may also be
secondarily affected. Regression analysis showed that plasma
cholesterol correlated with systolic blood pressure and with leukocyte
affinity for dexamethasone. Correlations of GR binding characteristics
with other variables may indicate a role for glucocorticoid hormones in
electrolyte homeostasis. Glucocorticoid activity was not a major
determinant of blood pressure or body fat distribution within the
narrow physiological limits of our volunteers, but may be one of
several genetic determinants in the pathogenesis of cardiovascular
disease.
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Footnotes |
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2 Awarded fellowships by the Society for Endocrinology (U.K.) and the
British Hypertension Society.
Received October 20, 1997.
Revised February 2, 1998.
Accepted February 11, 1998.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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- and
3ß- hydroxysteroid dehydrogenase and 5- and 5ß-reductase
pathways of aldosterone in male rats. Steroids. 55:52–58.[CrossRef][Medline]
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