Glucocorticoids and mineralocorticoids are members of the corticosteroid hormone
family, synthesized in the adrenal gland from the precursor sterol cholesterol via
the intermediate pregnenolone (Figure 1.1 ). The principal glucocorticoid in
humans is cortisol (in rodents corticosterone) and the principal mineralocorticoid
is aldosterone. Sharing a common synthesis pathway, cortisol and aldosterone are
structurally similar (Figure 1.1 ), and exhibit a degree of cross - receptor affi nity and
function. Nevertheless, small differences in structure permit important differ-
ences in physiological function. Aldosterone classically acts via the mineralocorti-
coid receptor ( MR ) to promote sodium transport in the kidney and gut, thereby
regulating long - term electrolyte homeostasis and blood pressure control. Cortisol,
by comparison, exhibits a wide range of metabolic and stress - related response
effects.
Synthesis of the Corticosteroids
Steroid synthesis occurs principally in the adrenal gland but also occurs in the
steroidogenic cells of the testes, ovary, placenta and brain. The intramitochondrial
delivery of cholesterol is the rate - limiting step for steroid synthesis and is mediated
by steroidogenic acute regulatory protein ( StAR ) [1] ). Defects in cholesterol trans-
port associated with mutations in StAR [2] cause the autosomal recessive disorder
of lipoid congenital adrenal hyperplasia ( CAH ; Online Mendelian Inheritance in
Man ( OMIM ) #201710). This rare condition presents with large adrenal glands
containing high levels of cholesterol. Lipoid CAH is lethal within a few days
without hormone replacement therapy. Over 30 mutations in StAR have been
reported to cause lipoid CAH, all of which result in varying degrees of defe c tive
cholesterol transport (for review, see [3] ). Mice null for StAR, generated by
homologous recombination, emphasize the key role of this protein. Homozygous
null pups fail to thrive and die within a week of birth: corticosterone and aldoste-
rone levels are very low despite elevated ACTH (adrenal corticotropic hormone)
and CRH (corticotropin - releasing hormone) [4] . Lipoid CAH can also arise from
mutations in P450scc [5] , an enzyme that cleaves cholesterol to produce pregnen-
olone – the common precursor for both cortisol and aldosterone synthesis (Figure
1.1 ). Indeed the biosysthetic pathways of both share a number of intermediates
and enzymes (Figure 1.1 ), becoming fully exclusive only at 11 - deoxycortisol ( DOC ;
cortisol pathway) and 11 - deoxycorticoisteroid (aldosterone pathway). In rodents,
exclusivity occurs at 11 - deoxycorticoisteroid (Figure 1.1b ).
The fi nal step in cortisol synthesis, the conversion of DOC to cortisol, is cata-
lyzed by 11 β - hydroxylase (CYP11B1 gene), while the fi nal three stages of aldoste-
rone synthesis require aldosterone synthase (CYP11B2 gene). There is a differential
spatial expression of these two enzymes in the cortex of the adrenal gland which
is divided into three distinct zones: zona glomerulosa, zona fasciculata and
zona reticularis. Cortisol is synthesized primarily in the zona fasciculata, with a
small amount being produced by neighboring cells in the zona reticularis. 11 β -
Hydroxylase is present in both these zones. Aldosterone is produced in the zona
glomerulosa, where aldosterone synthase expression is exclusively expressed.
Glucocorticoid remedial hypertension ( GRA ; OMIM #103900) is an autosomal
dominant disorder that occurs when there is unequal crossing over between
CYP11B1 and CYP11B2, which are highly homologous and located in tandem at
chromosome 8q24.3, approximately 45 kb apart [6] . In this situation, a chimeric
gene is created in which the 5’ regulatory regions of the 11 β - hydroxylase gene are
fused to the coding sequence of the aldosterone synthase gene. There is ectopic
expression of the aldosterone synthase in the zona fasciculata, which is now
strongly controlled by ACTH . GRA presents with constitutive release of aldoste-
rone and hypertension associated with sodium retention and potassium wasting.
Administration of exogenous glucocorticoids suppresses the HPA axis and allevi-
ates the symptoms (see Section 1.2.2 and Figure 1.3 ).
CAH (OMIM +201910) is an autosomal recessive disorder of cortisol synthe sis
in which patients have low levels of cortisol and accumulation of DOC and 11 -
deoxycorticosterone. Approximately 11% of CAH arises from mutations in
CYP11B1, the majority being caused by loss of 21 - hydroxylase function. Regardless
of genetic causality, CAH is associated with neonatal lethality, perhaps leading to
an underestimation of the prevalence of the syndrome. Hypertension (DOC is a
potent mineralocorticoid, see below) and symptoms of androgen excess, such as
precocious puberty and the development of intersexual genitalia, are also features.
The only mouse model of CAH available is the H - 2(aw) strain which carries a
variety of loss - of - function mutations in 21 - hydroxylase [7, 8] . Homozygosity for the
mutation causes neonatal death; mice heterozygous for mutations have compro-
mised steroidogenesis and faithfully reproduce CAH.
Mutations in CYP11B2 cause the autosomal disorder of corticosterone methyox-
idase defi ciency ( CMO ), types 1 and 2 [9] . In CMO1 (OMIM #203400), there is no
enzyme activity and aldosterone is undetectable. Patients have marked growth
retardation and fail to thrive. Altered renal electrolyte balance leads to hyponatre-
mia and hyperkalemia, and hypotension is evident. This is presumably secondary
to volume depletion; however, since activation of MR in vascular smooth muscle
potentiates the action of vasoconstrictors (see below), a contribution of vasodilation
to the hypotension cannot be discounted. CMO2 (OMIM #610600) is a milder
form of the disease: mutations impair but do not ablate aldosterone synthase activ-
ity. Lee et al. have modeled CMO1 in the mouse, replacing the fi rst two of nine
exons with enhanced green fl uorescent protein ( EGFP ), thereby creating a gene
expression reporter while concomitantly abolishing enzyme activity [10] . cyp11b2
null mice were born in normal Mendelian ratios, but a third of the homozygous
null animals died prior to weaning, with the rest showing marked retardation of
growth, hyperkalemia and altered renal electrolyte handling [10, 11] . Plasma renin
activity was elevated (45 - fold) in cyp11b2 null mice, and renin expression was
induced in both the zona glomerulosa and fasciculata of the adrenal gland. That
these changes failed to maintain blood pressure (null mice were mildly hypoten-
sive), despite the high levels of angiotensin ( Ang ) II, underscores the essential role
for aldosterone in blood pressure homeostasis. Salt supplementation rescued the
electrolyte disturbances but did not correct blood pressure. In experimental
animals, adrenalectomy or genetic ablation of MR will cause death unless salt
therapy is administered. Aldosterone synthase null mice do not require salt supple-
ments to survive with only modestly compromised blood pressure regulation, the
implication being that a degree of MR activation persists. The cyp11b2 null
mouse has provided important data concerning the role and regulation of
aldosterone synthesis. Induction of the EGFP construct was used to indicate gene
activation. Surprisingly the strongest signals were present in the transition zone
between cortex and medulla. It was demonstrated that this zone was rich in cells
undergoing apoptotic cell death, suggesting that abnormal aldosterone synthesis
has an extensive effect on adrenal gland structure and function. In addition to the
expected expansion of the zona glomerulosa, cortical architecture becomes disor-
ganized and there is signifi cant accumulation of lipid in steroidogenic cells.
Angiotensinogen, primarily synthesized in the liver, is cleaved by the aspartyl
protease renin to produce Ang I. This is further cleaved by angiotensin - converting
enzyme ( ACE ) to yield the octapeptide, Ang II. Ang II, acting via AT
1
and AT
2
receptors, will increase blood pressure due to effects on renal sodium reabsorp tion
and vascular resistance. Furthermore, the RAS is a biologically signifi cant
regulator of angiogenesis [13] . Therefore, Ang II is an important cardiovascular
hormone in its own right, quite separately from its effects on aldosterone synthe-
sis, as covered in Section 3.1 .
Ang II, and its metabolite Ang III, rapidly stimulate aldosterone production by
activation of both early and late stages of steroid biosynthesis [14] . Both angioten-
sins are equally effi cacious, but Ang II is present in the circulation at much higher
concentrations and is, therefore, more important.
Classically, the RAS operates at a systemic level. Recent evidence, however,
demonstrates that the RAS can operate independently at the level of the tissue and
exert powerful cardiovascular effects quite independently of the systemic system
[15] . Although there are no strong quantitative trait locus associations between the
RAS and primary hypertension, the involvement of this system in the misregula-
tion of blood pressure is undisputed: the benefi cial effects of ACE inhibitors and
AT 1
receptor blockers in patients with cardiovascular disease has been demon-
strated many times in large - scale clinical trials [16] . More recently, a second form
of ACE (ACEII) has been implicated in cardiovascular disease [17] and is a novel
therapeutic target. Similarly, the new renin inhibitor, aliskiren, is effective in the
treatment of moderate hypertension, although long - term outcome data are not yet
available [18] . As for other systems, the use of transgenic animals has clearly
demonstrated the major role of the RAS in cardiovascular homeostasis (for a
detailed review of this subject, see [19] ). Nevertheless, in the majority of these
models, the primary abnormality in blood pressure relates to alterations in circulat-
ing Ang II, rather than aldosterone. That aldosterone synthesis occurs despite
compromised RAS indicates the important regulatory role of plasma potassium
levels. This is further supported by the observation that the circadian rhythm of
aldosterone secretion does not coincide with that for renin, but for potassium.
An increase in plasma potassium concentration increases the synthesis of aldo-
sterone and, conversely, potassium depletion reduces aldosterone synthesis. The
regulation of aldosterone synthesis by potassium is very sensitive: changes of
± 0.1 mM can alter the rate of production independently of either Ang II or plasma
sodium [12] . There is, moreover, reciprocal regulation: if plasma potassium rises,
the rapid increase in aldosterone synthesis promotes kaliuresis and a redistribu-
tion of potassium from the extracellular fl uid into the cytosol, thereby returning
plasma potassium levels to normal [20] . This feedback loop is so persuasive that
it can, under conditions of sodium depletion for example, uncouple the secretion
of aldosterone from control by Ang II [21] . Thus, the sodium - retaining (and
pressor) effects of Ang II may be more important for blood pressure homeostasis
than the effects of aldosterone on either the kidney or the vasculature, with the
latter acting principally as a regulator of potassium [20] .
family, synthesized in the adrenal gland from the precursor sterol cholesterol via
the intermediate pregnenolone (Figure 1.1 ). The principal glucocorticoid in
humans is cortisol (in rodents corticosterone) and the principal mineralocorticoid
is aldosterone. Sharing a common synthesis pathway, cortisol and aldosterone are
structurally similar (Figure 1.1 ), and exhibit a degree of cross - receptor affi nity and
function. Nevertheless, small differences in structure permit important differ-
ences in physiological function. Aldosterone classically acts via the mineralocorti-
coid receptor ( MR ) to promote sodium transport in the kidney and gut, thereby
regulating long - term electrolyte homeostasis and blood pressure control. Cortisol,
by comparison, exhibits a wide range of metabolic and stress - related response
effects.
Synthesis of the Corticosteroids
Steroid synthesis occurs principally in the adrenal gland but also occurs in the
steroidogenic cells of the testes, ovary, placenta and brain. The intramitochondrial
delivery of cholesterol is the rate - limiting step for steroid synthesis and is mediated
by steroidogenic acute regulatory protein ( StAR ) [1] ). Defects in cholesterol trans-
port associated with mutations in StAR [2] cause the autosomal recessive disorder
of lipoid congenital adrenal hyperplasia ( CAH ; Online Mendelian Inheritance in
Man ( OMIM ) #201710). This rare condition presents with large adrenal glands
containing high levels of cholesterol. Lipoid CAH is lethal within a few days
without hormone replacement therapy. Over 30 mutations in StAR have been
reported to cause lipoid CAH, all of which result in varying degrees of defe c tive
cholesterol transport (for review, see [3] ). Mice null for StAR, generated by
homologous recombination, emphasize the key role of this protein. Homozygous
null pups fail to thrive and die within a week of birth: corticosterone and aldoste-
rone levels are very low despite elevated ACTH (adrenal corticotropic hormone)
and CRH (corticotropin - releasing hormone) [4] . Lipoid CAH can also arise from
mutations in P450scc [5] , an enzyme that cleaves cholesterol to produce pregnen-
olone – the common precursor for both cortisol and aldosterone synthesis (Figure
1.1 ). Indeed the biosysthetic pathways of both share a number of intermediates
and enzymes (Figure 1.1 ), becoming fully exclusive only at 11 - deoxycortisol ( DOC ;
cortisol pathway) and 11 - deoxycorticoisteroid (aldosterone pathway). In rodents,
exclusivity occurs at 11 - deoxycorticoisteroid (Figure 1.1b ).
The fi nal step in cortisol synthesis, the conversion of DOC to cortisol, is cata-
lyzed by 11 β - hydroxylase (CYP11B1 gene), while the fi nal three stages of aldoste-
rone synthesis require aldosterone synthase (CYP11B2 gene). There is a differential
spatial expression of these two enzymes in the cortex of the adrenal gland which
is divided into three distinct zones: zona glomerulosa, zona fasciculata and
zona reticularis. Cortisol is synthesized primarily in the zona fasciculata, with a
small amount being produced by neighboring cells in the zona reticularis. 11 β -
Hydroxylase is present in both these zones. Aldosterone is produced in the zona
glomerulosa, where aldosterone synthase expression is exclusively expressed.
Glucocorticoid remedial hypertension ( GRA ; OMIM #103900) is an autosomal
dominant disorder that occurs when there is unequal crossing over between
CYP11B1 and CYP11B2, which are highly homologous and located in tandem at chromosome 8q24.3, approximately 45 kb apart [6] . In this situation, a chimeric
gene is created in which the 5’ regulatory regions of the 11 β - hydroxylase gene are
fused to the coding sequence of the aldosterone synthase gene. There is ectopic
expression of the aldosterone synthase in the zona fasciculata, which is now
strongly controlled by ACTH . GRA presents with constitutive release of aldoste-
rone and hypertension associated with sodium retention and potassium wasting.
Administration of exogenous glucocorticoids suppresses the HPA axis and allevi-
ates the symptoms (see Section 1.2.2 and Figure 1.3 ).
CAH (OMIM +201910) is an autosomal recessive disorder of cortisol synthe sis
in which patients have low levels of cortisol and accumulation of DOC and 11 -
deoxycorticosterone. Approximately 11% of CAH arises from mutations in
CYP11B1, the majority being caused by loss of 21 - hydroxylase function. Regardless
of genetic causality, CAH is associated with neonatal lethality, perhaps leading to
an underestimation of the prevalence of the syndrome. Hypertension (DOC is a
potent mineralocorticoid, see below) and symptoms of androgen excess, such as
precocious puberty and the development of intersexual genitalia, are also features.
The only mouse model of CAH available is the H - 2(aw) strain which carries a
variety of loss - of - function mutations in 21 - hydroxylase [7, 8] . Homozygosity for the
mutation causes neonatal death; mice heterozygous for mutations have compro-
mised steroidogenesis and faithfully reproduce CAH.
Mutations in CYP11B2 cause the autosomal disorder of corticosterone methyox-
idase defi ciency ( CMO ), types 1 and 2 [9] . In CMO1 (OMIM #203400), there is no
enzyme activity and aldosterone is undetectable. Patients have marked growth
retardation and fail to thrive. Altered renal electrolyte balance leads to hyponatre-
mia and hyperkalemia, and hypotension is evident. This is presumably secondary
to volume depletion; however, since activation of MR in vascular smooth muscle
potentiates the action of vasoconstrictors (see below), a contribution of vasodilation
to the hypotension cannot be discounted. CMO2 (OMIM #610600) is a milder
form of the disease: mutations impair but do not ablate aldosterone synthase activ-
ity. Lee et al. have modeled CMO1 in the mouse, replacing the fi rst two of nine
exons with enhanced green fl uorescent protein ( EGFP ), thereby creating a gene
expression reporter while concomitantly abolishing enzyme activity [10] . cyp11b2
null mice were born in normal Mendelian ratios, but a third of the homozygous
null animals died prior to weaning, with the rest showing marked retardation of
growth, hyperkalemia and altered renal electrolyte handling [10, 11] . Plasma renin
activity was elevated (45 - fold) in cyp11b2 null mice, and renin expression was
induced in both the zona glomerulosa and fasciculata of the adrenal gland. That
these changes failed to maintain blood pressure (null mice were mildly hypoten-
sive), despite the high levels of angiotensin ( Ang ) II, underscores the essential role
for aldosterone in blood pressure homeostasis. Salt supplementation rescued the
electrolyte disturbances but did not correct blood pressure. In experimental
animals, adrenalectomy or genetic ablation of MR will cause death unless salt
therapy is administered. Aldosterone synthase null mice do not require salt supple-
ments to survive with only modestly compromised blood pressure regulation, the
implication being that a degree of MR activation persists. The cyp11b2 null
mouse has provided important data concerning the role and regulation of
aldosterone synthesis. Induction of the EGFP construct was used to indicate gene
activation. Surprisingly the strongest signals were present in the transition zone
between cortex and medulla. It was demonstrated that this zone was rich in cells
undergoing apoptotic cell death, suggesting that abnormal aldosterone synthesis
has an extensive effect on adrenal gland structure and function. In addition to the
expected expansion of the zona glomerulosa, cortical architecture becomes disor-
ganized and there is signifi cant accumulation of lipid in steroidogenic cells.
Angiotensinogen, primarily synthesized in the liver, is cleaved by the aspartyl
protease renin to produce Ang I. This is further cleaved by angiotensin - converting
enzyme ( ACE ) to yield the octapeptide, Ang II. Ang II, acting via AT
1
and AT
2
receptors, will increase blood pressure due to effects on renal sodium reabsorp tion
and vascular resistance. Furthermore, the RAS is a biologically signifi cant
regulator of angiogenesis [13] . Therefore, Ang II is an important cardiovascular
hormone in its own right, quite separately from its effects on aldosterone synthe-
sis, as covered in Section 3.1 .
Ang II, and its metabolite Ang III, rapidly stimulate aldosterone production by
activation of both early and late stages of steroid biosynthesis [14] . Both angioten-
sins are equally effi cacious, but Ang II is present in the circulation at much higher
concentrations and is, therefore, more important.
Classically, the RAS operates at a systemic level. Recent evidence, however,
demonstrates that the RAS can operate independently at the level of the tissue and
exert powerful cardiovascular effects quite independently of the systemic system
[15] . Although there are no strong quantitative trait locus associations between the
RAS and primary hypertension, the involvement of this system in the misregula-
tion of blood pressure is undisputed: the benefi cial effects of ACE inhibitors and
AT 1
receptor blockers in patients with cardiovascular disease has been demon-
strated many times in large - scale clinical trials [16] . More recently, a second form
of ACE (ACEII) has been implicated in cardiovascular disease [17] and is a novel
therapeutic target. Similarly, the new renin inhibitor, aliskiren, is effective in the
treatment of moderate hypertension, although long - term outcome data are not yet
available [18] . As for other systems, the use of transgenic animals has clearly
demonstrated the major role of the RAS in cardiovascular homeostasis (for a
detailed review of this subject, see [19] ). Nevertheless, in the majority of these
models, the primary abnormality in blood pressure relates to alterations in circulat-
ing Ang II, rather than aldosterone. That aldosterone synthesis occurs despite
compromised RAS indicates the important regulatory role of plasma potassium
levels. This is further supported by the observation that the circadian rhythm of
aldosterone secretion does not coincide with that for renin, but for potassium.
An increase in plasma potassium concentration increases the synthesis of aldo-
sterone and, conversely, potassium depletion reduces aldosterone synthesis. The
regulation of aldosterone synthesis by potassium is very sensitive: changes of
± 0.1 mM can alter the rate of production independently of either Ang II or plasma
sodium [12] . There is, moreover, reciprocal regulation: if plasma potassium rises,
the rapid increase in aldosterone synthesis promotes kaliuresis and a redistribu-
tion of potassium from the extracellular fl uid into the cytosol, thereby returning
plasma potassium levels to normal [20] . This feedback loop is so persuasive that
it can, under conditions of sodium depletion for example, uncouple the secretion
of aldosterone from control by Ang II [21] . Thus, the sodium - retaining (and
pressor) effects of Ang II may be more important for blood pressure homeostasis
than the effects of aldosterone on either the kidney or the vasculature, with the
latter acting principally as a regulator of potassium [20] .
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