ΥΠΟΔΟΧΕΑΣ
ΑΛΑΤΟΚΟΡΤΙΚΟΕΙΔΩΝ
ΧΑΡΑΚΤΗΡΙΣΤΙΚΑ
&
ΠΛΕΙΟΤΡΟΠΕΣ ΔΡΑΣΕΙΣ
23 Ιανουαρίου 2014
Κωνσταντίνος Π. Μακαρίτσης
Παθολογική Κλινική
Πανεπιστημίου Θεσσαλίας
ΕΙΣΑΓΩΓΗ
Η αλδοστερόνη απομονώθηκε για πρώτη φορά το
1953 και παράγεται στη σπειροειδή ζώνη του
φλοιού των επινεφριδίων.
Μείζονα ερεθίσματα για έκκριση αλδοστερόνης:
Αγγειοτενσίνη ΙΙ
Επίπεδα του Κ+ του πλάσματος
Η αλδοστερόνη αυξάνει την επαναρρόφηση Να+
και ύδατος από το τελικό άπω εσπειραμένο και τη
φλοιώδη μοίρα του αθροιστικού σωληναρίου του
νεφρού.
NCCT
ENaC
Aldosterone
NHEs
NKCC2
N Engl J Med
Sodium Channels and Transporters
• Approximately 2-3% of filtered
sodium is reabsorbed in the cortical
collecting tubule via the epithelial Na
channel (ENaC).
• ENaC is composed of 3 subunits, α, β,
γ. All 3 subunits are required for a
fully functional channel.
Aldosterone-Regulated Transport - Cortical Collecting Tubule
Aldosterone-Regulated Transport - Cortical Collecting Tubule
Amiloride
Triamterene
N Engl J Med 1999;340:1177-87.
Spironolactone
Eplerenone
Sodium Channels and Transporters
• Regulation
of
Na
reabsorption
depends on the number of channels
inserted in the cell membrane.
• Vasopressin (via increased cAMP) and
aldosterone
(via
serum
and
glucocorticoid-regulated
kinase
[SGK]) increase the density of
channels at the cell surface.
Regulation of ENaC membrane expression
α β γ
MR
Insulin
Mineralocorticoid
Receptor-MR
Στοιχεία Παθοφυσιολογίας
Στοιχεία Παθοφυσιολογίας
Η συγκέντρωση της αλδοστερόνης στο πλάσμα
είναι πολύ μικρή (<1nmol/L) και κυκλοφορεί
συνδεδεμένη με την αλβουμίνη σε ποσοστό περίπου
50%.
Αντιθέτως, τα φυσικά γλυκοκορτικοειδή –
κορτιζόλη και κορτικοστερόνη – κυκλοφορούν
συνδεδεμένα με την τρανσκορτίνη (CBG) και την
αλβουμίνη σε ποσοστό περίπου 95%
Τα επίπεδα της κορτιζόλης στο πλάσμα είναι από
100-1000 φορές υψηλότερα από τα επίπεδα της
αλδοστερόνης.
Στοιχεία Παθοφυσιολογίας
Ο Mineralocorticoid Receptor-MR είναι μέλος
της οικογένειας των πυρηνικών υποδοχέων των
στεροειδών/θυρεοειδικών/ρετινοϊκών/λιπιδικών/
”ορφανών” υποδοχέων, που απαρτίζεται από 49
μέλη στον άνθρωπο.
Ο MR μεταβάλλει την έκφραση συγκεκριμένων
γονιδίων, αλλά έχει δειχθεί ότι συμμετέχει και
στις καλούμενες ταχείες μη γονιδιωματικές
δράσεις (rapid non-genomic effects).
Hypertension. 2011;57:1019-1025.
Aldosterone signaling
PI3K
Rapid
non-Genomic
Effects
Genomic Effects
Hypertension. 2011;57:1019-1025.
Στοιχεία Παθοφυσιολογίας
Ο MR εκφράζεται στα επιθηλιακά κύτταρα
νεφρού
κατιόντος κόλου
σιελογόνων και ιδρωτοποιών αδένων
Ωστόσο,
ο MR έχει εντοπιστεί και σε μη-επιθηλιακά κύτταρα
ιπποκάμπου
καρδιάς(καρδιακά μυϊκά κύτταρα,
ενδοθηλιακά,ινοβλάστες, μακροφάγα)
αγγείων (ενδοθηλιακά και λεία μυϊκά κύτταρα)
Mineralocorticoid Receptor-MR
Έχει διαπιστωθεί, ότι ο MR παρουσιάζει
παρόμοια χημική συγγένεια ως προς τη δέσμευση
της αλδοστερόνης και της κορτιζόλης.
Πώς η αλδοστερόνη ενεργοποιεί επιλεκτικά τον
MR στα επιθηλιακά κύτταρα, καθώς αφενός δεν
υπάρχει εκλεκτικότητα στο επίπεδο του
υποδοχέα και αφετέρου τα επίπεδα της
κορτιζόλης στο πλάσμα είναι από 100-1000
φορές υψηλότερα από τα επίπεδα της
αλδοστερόνης;;;
Molecular and Cellular Endocrinology 350 (2012) 289–298.
Mineralocorticoid Receptor-MR
Η απάντηση στο ερώτημα αυτό προέκυψε με την
ανακάλυψη του ρόλου του ενζύμου 11βHSD2 (11βhydroxysteroid dehydrogenase type 2), το οποίο
εκφράζεται σε υψηλές συγκεντρώσεις μαζί με τον
MR στα επιθηλιακά κύτταρα, αλλά και στο τοίχωμα
των αγγείων και στον πυρήνα της μονήρους
δεσμίδας (NTS).
Το ένζυμο αυτό (11βHSD2) καταλύει τη μετατροπή
της κορτιζόλης σε κορτιζόνη, ενώ δεν επηρεάζει
την αλδοστερόνη. Η κορτιζόνη δεν ενεργοποιεί τον
MR, οπότε διευκολύνεται η επίδραση της
αλδοστερόνης στον MR.
Molecular and Cellular Endocrinology 350 (2012) 289–298.
CHIMERIC
GENE
GRA
Congenital
Adrenal
Hyperplasia
11β-HSD2*
* 11β-Hydroxy Steroid Dehydrogenase2
SAME Syndrome
Glycyrrhizic acid
Carvenoxolone
Mineralocorticoid Receptor-MR
Hypertens Res 2004; 27: 781–789.
Mineralocorticoid Receptor-MR
It has been subsequently shown that under
normal conditions most epithelial MRs are
occupied (~ 90%), but not activated by normal
levels of endogenous glucocorticoids.
MR–glucocorticoid complexes are presumably
held inactive under normal conditions by the
obligate co-generation of high levels of NADH,
shown to be an inhibitor of transcription by corepressor activation in other transcriptional
systems.
Biochimica et Biophysica Acta 1802 (2010) 1188–1192.
Mineralocorticoid Receptor-MR
Under conditions of tissue damage, reactive
oxygen species generation and intracellular
redox
change,
cortisol
becomes
a
mineralocorticoid receptor agonist, in the
vessel
wall
and
heart,
mimicking
the
deleterious effects of elevated aldosterone
inappropriate for salt status.
Biochimica et Biophysica Acta 1802 (2010) 1188–1192.
MR and Evolution
Aldosterone is postulated to have played a
key role in the phylogenic transition from aquatic
fishes to terrestrial tetrapods, given its major
epithelial effects on sodium retention and
potassium excretion.
Thus, the aldosterone/MR pathway enabled
animals to retain sodium in the body to sustain
life on land, where there was little salt.
In our modern industrialized societies,
however, an abundance of salt and a pandemic of
obesity
synergistically
cause
inappropriate
activation of the aldosterone/MR system, that
causes salt-sensitive hypertension and cardiorenal
Hypertension 2010;55:813-818.
disease.
Phylogenetic perspectives on the aldosterone/MR system
Clin Exp Nephrol (2010) 14:303–314.
CVD
Effects of Aldosterone in Relation to
Sodium Status
High levels of aldosterone in response to
dietary salt restriction, promotes renal
sodium
conservation,
but
has
no
cardiovascular consequences.
When
aldosterone
is
produced
in
inappropriate amounts for the level of sodium
status, it results in excessive renal sodium
retention, potassium wasting, hypertension,
and cardiovascular damage.
N Engl J Med. 2004;351:8-10.
Physiologic and Pathophysiologic Effects of Aldosterone
on the Kidney and Heart in Relation to Dietary Salt levels
High
Low
N Engl J Med. 2004;351:8-10.
Is aldosterone a cardiovascular risk factor?
In primary aldosteronism and chronic high salt
intake, aldosterone levels are inappropriate
high for sodium status and aldosterone is
clearly a cardiovascular risk factor.
In essential hypertension and heart failure it
might
be
cortisol
which
activates
mineralocorticoid receptors.
Thus, mineralocorticoid receptor activation,
not aldosterone, is the risk factor.
Biochimica et Biophysica Acta 1802 (2010) 1188–1192.
Deleterious actions of Increased MR Activation
Increased MR
Activation
Cardiology in Review 2005;13:118–124.
MR, Aldosterone and
Blood Pressure
MR, Aldosterone and blood pressure
Aldosterone secretion is raised in response to
sodium deficiency.
Secretion of endogenous ouabain is raised in
response to sodium loading.
The role of aldosterone is to retain sodium in
the face of chronic deficiency.
The role of endogenous ouabain is to excrete
sodium, via a pressure natriuresis effect.
Endogenous ouabain increases blood pressure.
MR, Aldosterone and blood pressure
Aldosterone secretion is raised in response to
sodium deficiency.
Secretion of endogenous ouabain is raised in
response to sodium loading.
The role of aldosterone is to retain sodium in
the face of chronic deficiency.
The role of endogenous ouabain is to excrete
sodium, via a pressure natriuresis effect.
Endogenous ouabain increases blood pressure.
MR, Aldosterone and blood pressure
It is possible that the blood pressure
elevating effects of aldosterone reflect not
only direct effects on the vessel wall but also
sodium retention with the resultant elevation
of endogenous ouabain secretion.
The combined elevation of aldosterone and
endogenous ouabain levels in response to
salt/mineralocorticoid imbalance may thus be
an explanation of the hypertension produced.
Pathways of salt-sensitive hypertension
Ouabain
___
NCX1
Nature Medicine, Nov 2004
___
Ouabain
Aldosterone
N Engl J Med. 2007;356:1966-78.
MR in vascular
constriction and
relaxation
MR in vascular constriction and relaxation
In all studies, the effects of Aldo are MRdependent, implicating vascular MR in direct
regulation of vascular tone.
MR activation in vascular SMC and EC increases
ROS and decreases bioavailable NO and thus
would
be
expected
to
promote
VSMC
contraction by decreasing GC activity.
Molecular and Cellular Endocrinology 350 (2012) 256–265.
British Journal of Pharmacology (2011) 163 1163–1169.
MR in vascular constriction and relaxation
Interestingly, when Aldo is infused into vessels
intraluminally to target the endothelium a
vasodilator response was found, that required
the presence of the endothelium, MR, and NO
generation via NOS.
Co-incubation with NOS inhibitors resulted in a
loss
of
vasodilation
and/or
enhanced
contraction, again implicating endothelial MR in
vasodilation and SMC MR in vasoconstriction.
Molecular and Cellular Endocrinology 350 (2012) 256–265.
British Journal of Pharmacology (2011) 163 1163–1169.
MR in vascular constriction and relaxation
The effects of MR activation on vascular
reactivity in “healthy” humans also remains
somewhat controversial due to conflicting
results from clinical studies with many
demonstrating a constrictive response and
some showing vascular relaxation.
The discrepancies may be due to differences in
the vascular health of the study participants in
addition to differences in dose and duration of
Aldo infusion.
Molecular and Cellular Endocrinology 350 (2012) 256–265.
British Journal of Pharmacology (2011) 163 1163–1169.
MR in vascular constriction and relaxation
When patients with underlying cardiovascular
diseases are studied, including patients with
atherosclerosis,
heart
failure,
and
hypertension, the data are quite consistent
with
MR-activation
systemic
vascular
promoting
resistance
and
increased
reduced
forearm blood flow.
Molecular and Cellular Endocrinology 350 (2012) 256–265.
British Journal of Pharmacology (2011) 163 1163–1169.
MR in vascular constriction and relaxation
MR in vascular constriction and relaxation
Taken together, these data support that in
healthy vessels, acute MR activation may evoke
endothelium - dependent, NO - mediated
vasodilation
while,
in
the
presence
of
endothelial dysfunction, vascular injury, or high
vascular oxidative stress (as in patients with
cardiovascular risk factors), MR activation
promotes vasoconstriction.
Molecular and Cellular Endocrinology 350 (2012) 256–265.
British Journal of Pharmacology (2011) 163 1163–1169.
MR and Vascular
Oxidative Stress
MR, Aldosterone and Vascular Oxidative Stress
The interaction of ROS with NO also decreases
the bioavailability of NO resulting in impaired ECdependent vasorelaxation and the peroxinitrite
formed can directly alter many vascular cell
functions.
Aldosterone also produces oxidative stress and
endothelial
dysfunction
by
decreasing
the
expression of G6PD, which reduces NADP+ to
NADPH.
Molecular and Cellular Endocrinology 350 (2012) 256–265.
Clinical Science (2007) 113, 267–278.
MR, Aldosterone and Vascular Oxidative Stress
peroxinitrite
Molecular and Cellular Endocrinology 350 (2012) 256–265.
Clinical Science (2007) 113, 267–278.
MR, Aldosterone and Vascular Oxidative Stress
MR and Vascular
Inflammation
MR, Aldosterone and Vascular Inflammation
Direct activation of MR has been shown to
promote inflammatory gene expression.
MR activation promotes expression of:
adhesion molecules ICAM1 and VCAM1
interleukin-16
cytotoxic T-lymphocyte-ass. Protein 4
Infusion of Aldo increased circulating IL-6
Treatment with spironolactone reduced MCP-1 and
PAI-1 levels
Molecular and Cellular Endocrinology 350 (2012) 256–265.
MR, Aldosterone and Vascular Inflammation
Vascular MR activation participates in the
inflammatory
response
by
up-regulating
adhesion molecules, chemokines, cytokines,
and
growth
factors
that
promote
the
recruitment and activation of inflammatory
cells.
Molecular and Cellular Endocrinology 350 (2012) 256–265.
MR and Vascular
Remodeling
MR, Aldosterone and Vascular Remodeling
Multiple animal models support that Aldo
exacerbates vascular remodeling in association
with endothelial damage in vivo and these effects
are reversed by MR antagonists.
Human studies have shown that patients with
primary
aldosteronism
have
significantly
increased vascular medial thickness and narrowed
vessel lumens compared to patients with similar
degrees of essential hypertension and other
forms of secondary hypertension.
Molecular and Cellular Endocrinology 350 (2012) 256–265.
MR, Aldosterone and Vascular Remodeling
Molecular and Cellular Endocrinology 350 (2012) 256–265.
Mineralocorticoid receptors in vascular dysfunction and disease
Molecular and Cellular Endocrinology 350 (2012) 256–265.
MR and Myocardial
Remodeling
MR, Aldosterone and Myocardial Remodeling
Cardiac tissue remodeling is characterised by:
•Accumulation of collagen fibers types I & III
•Cardiomyocyte hypertrophy
•Fibroblast proliferation
•Remodeling of the structural electrical coupling
components of the myocardium
Molecular and Cellular Endocrinology 350 (2012) 248–255.
MR, Aldosterone and Myocardial Remodeling
It is widely accepted that collagen synthesis is
stimulated by a number of signaling molecules,
including:
Cytokines (IL-13, IL-21, TGF-b1)
Chemokines (MCP-1 and MIP-1b)
VEGF
Osteopontin
PAI-1
Endothelin-1
Molecular and Cellular Endocrinology 350 (2012) 248–255.
MR, Aldosterone and Myocardial Remodeling
Numerous studies have shown that, in the
presence of a high salt diet, aldosterone increases
interstitial and perivascular cardiac fibrosis.
Conversely, aldosterone-infused rats on a low salt
diet did not.
The cardiac response to aldosterone is a direct,
MR-dependent response, that is independent of
the effect on blood pressure and the circulating
and tissue RAS.
Molecular and Cellular Endocrinology 350 (2012) 248–255.
Aldosterone effect on the expression of profibrotic factors
Clinical Science (2007) 113, 267–278.
Macrophage MR are critical for the activation of tissue macrophages and the
onset of fibrosis whereas vascular MR (endothelial cell and vascular smooth
muscle cell, VSMC) and macrophage MR contribute to the increased systolic
blood pressure response.
Molecular and Cellular Endocrinology 350 (2012) 248–255.
MR and
Heart Failure
MR, Aldosterone and Heart Failure
Consistent with experimental studies, several
clinical trials (RALES, EPHESUS, EMPHASIS-HF),
have demonstrated a reduced mortality and
morbidity when MR antagonists are included in the
treatment of moderate–severe heart failure.
The guidelines of American (ACC/AHA) and of the
European
(ESC)
Societies
of
Cardiology
recommend ACE inhibitors and beta-blockers as
class I indication, then angiotensin receptor
antagonists (ARBs) and MRAs.
Molecular and Cellular Endocrinology 350 (2012) 266–272.
Characteristics of studies with MR antagonists
Curr Heart Fail Rep (2011) 8:7–13.
Eur J Clin Invest 2012 DOI: 10.1111/j.
1365-2362.2012.02676.x
MR, Aldosterone and Heart Failure
Available evidence favors addition of MRA as the
next step in heart failure on ACE inhibitor
therapy rather than an ARB.
In two recent meta-analyses, mortality was
reduced by 25% (P=0.00001) with the addition of
MRA vs. to no significance with added ARB.
Thus, the data in aggregate (and cost) seem to
favor the addition of MRAs over ARBs.
However, despite the clear benefit of MRAs in
several classes of HF they remain underused.
Molecular and Cellular Endocrinology 350 (2012) 266–272.
MR and
Kidney Disease
MR, Aldosterone and Chronic Kidney Disease
In 1996 a landmark study by Greene et al.
reported that the protective effects of ACEI
and ARB in renal ablation model are reversed by
exogenous
aldosterone
infusion,
clearly
demonstrating that aldosterone plays a major
role in causing kidney injury independent of
angiotensin II.
Molecular and Cellular Endocrinology 350 (2012) 273–280.
MR, Aldosterone and Chronic Kidney Disease
Previous studies have shown the presence of
11bHSD2
in
the
glomeruli
and
cultured
podocytes, implying that aldosterone can directly
modulate the glomerular cell function through
MR.
Aldosterone/salt-treated animals exhibit heavy
proteinuria because of severe glomerular injury
resulting in glomerulosclerosis.
Molecular and Cellular Endocrinology 350 (2012) 273–280.
MR, Aldosterone and Chronic Kidney Disease
Almost
all
renal
parenchyma
are
affected
Vasculature
Glomeruli
Tubulointerstitium
Renal vascular changes significantly contribute
Transmural fibrinoid necrosis
Intimal thickening
Adventitial fibrosis
Molecular and Cellular Endocrinology 350 (2012) 273–280.
MR, Aldosterone and Chronic Kidney Disease
Aldosterone causes glomerular injury, especially
in podocytes that serve as the key filtration
barrier in the glomeruli.
Decreased glomerular expression of
nephrin
podocin
Increased glomerular expression of
desmin, a marker for podocyte damage
In addition, these changes were almost
completely prevented by the coadministration of
eplerenone.
Molecular and Cellular Endocrinology 350 (2012) 273–280.
Hypertension 2007;49:355–364.
Involvement of podocyte damage in the renal
dysfunction of aldosterone/salt-treated rats
24h Urinary Protein
Hypertension 2007;49:355–364.
Mechanisms of aldosterone/MR-induced kidney injury
Molecular and Cellular Endocrinology 350 (2012) 273–280.
MR blockade and Chronic Kidney Disease
Although hyperkalemia limits its use in renal
insufficiency, accumulating data indicate that
MR blockade can confer renoprotection.
Clinical studies involving relatively small numbers
of subjects reported that MR blockade
effectively reduces proteinuria in subjects with
hypertension, diabetes, and chronic kidney
diseases.
Other studies have shown that the combination
of an ACEI with spironolactone decreases
albuminuria more than the combination of an
ACEI with an ARB.
Molecular and Cellular Endocrinology 350 (2012) 273–280.
MR and the
Metabolic Syndrome
MR, Aldosterone and Metabolic Syndrome
Plasma aldosterone in women correlated directly
with visceral adipose tissue, and higher plasma
aldosterone values have also been reported in
patients with metabolic syndrome, which is
independent of plasma renin activity.
Accumulating studies have elucidated the close
relationship between aldosterone and obesity.
Molecular and Cellular Endocrinology 350 (2012) 273–280.
MR, Aldosterone and Metabolic Syndrome
The adipose tissue is an endocrine organ that
secretes a variety of adipokines.
Adipocytes are capable of stimulating adrenal
aldosterone synthesis through the secretion of
potent aldosterone-releasing factors (ARFs),
which are not yet identified.
Nonetheless, the adipose tissue does not
express 11βHSD2, and MR in adipocytes are
predominantly occupied by glucocorticoids which
have an essential function in adipocytes.
Molecular and Cellular Endocrinology 350 (2012) 273–280.
MR, Aldosterone and Metabolic Syndrome
Aldosterone-releasing factors (ARFs)
Molecular and Cellular Endocrinology 350 (2012) 281–288.
MR, Aldosterone and Metabolic Syndrome
There is a worse control of BP in obese than lean
hypertensives, which can also be related to
excessive aldosterone.
Aldosterone overproduction is an important
cause of resistant hypertension and MR blockade
has been shown to effectively reduce BP in such
patients.
Molecular and Cellular Endocrinology 350 (2012) 273–280.
MR, Aldosterone and Metabolic Syndrome
Adipocyte
type 1
Hypertension 2010;55:813-818.
Summary - MR and CardioRenal Disease
For 50 years aldosterone has been thought to act
primarily on the renal epithelia to regulate fluid
and electrolyte homeostasis.
The discovery in the 1980s that aldosterone had a
range of extrarenal MR receptors and actions,
especially in the heart and blood vessels, has
certainly renewed interest in the field of MR
antagonists.
Further studies will provide a clear understanding
of the mechanisms of the MRAs beneficial
effects in CV and Renal disease.
Molecular and Cellular Endocrinology 350 (2012) 266–272.
ΣΑΣ
ΕΥΧΑΡΙΣΤΩ
A hypothetical model of MR pathway activation
in type 2 metabolic syndrome (no hyperaldosteronism)
Metabolic syndrome
type 2
Molecular and Cellular Endocrinology 350 (2012) 273–280.
Hypertension 2010;55:813-818.