ΥΠΟΔΟΧΕΑΣ ΑΛΑΤΟΚΟΡΤΙΚΟΕΙΔΩΝ ΧΑΡΑΚΤΗΡΙΣΤΙΚΑ & ΠΛΕΙΟΤΡΟΠΕΣ ΔΡΑΣΕΙΣ

ΥΠΟΔΟΧΕΑΣ ΑΛΑΤΟΚΟΡΤΙΚΟΕΙΔΩΝ

ΧΑΡΑΚΤΗΡΙΣΤΙΚΑ&

ΠΛΕΙΟΤΡΟΠΕΣ ΔΡΑΣΕΙΣ

Κωνσταντίνος Π. ΜακαρίτσηςΠαθολογική Κλινική

Πανεπιστημίου Θεσσαλίας

23 Ιανουαρίου 2014

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.

ΕΙΣΑΓΩΓΗ

ENaCNCCT

NKCC2

NHEs

N Engl J Med

Aldosterone

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

AmilorideTriamteren

e

Spironolactone

EplerenoneX

X

N Engl J Med 1999;340:1177-87.

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

InsulinMR

α β γ

Mineralocorticoid Receptor-

MR

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.



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

Hypertension. 2011;57:1019-1025.

Rapid non-Genomic

Effects

Genomic Effects

PI3K


Ο MR εκφράζεται στα επιθηλιακά κύτταρα

νεφρούκατιόντος κόλου σιελογόνων και ιδρωτοποιών αδένων

Ωστόσο, ο MR έχει εντοπιστεί και σε μη-επιθηλιακά κύτταρα

ιπποκάμπουκαρδιάς(καρδιακά μυϊκά κύτταρα,

ενδοθηλιακά,ινοβλάστες, μακροφάγα)

αγγείων (ενδοθηλιακά και λεία μυϊκά κύτταρα)

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;;;

Mineralocorticoid Receptor-MR

Molecular and Cellular Endocrinology 350 (2012) 289–298.

Η απάντηση στο ερώτημα αυτό προέκυψε με την ανακάλυψη του ρόλου του ενζύμου 11βHSD2 (11β-hydroxysteroid 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.



11β-HSD2*

* 11β-Hydroxy Steroid Dehydrogenase2

SAME Syndrome

Glycyrrhizic acid Carvenoxolone

Congenital Adrenal

Hyperplasia

CHIMERIC GENE

GRA

Hypertens Res 2004; 27: 781–789.



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 co-repressor activation in other transcriptional systems. Biochimica et Biophysica Acta 1802 (2010) 1188–1192.


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.

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 disease.

MR and Evolution

Hypertension 2010;55:813-818.

Clin Exp Nephrol (2010) 14:303–314.

Phylogenetic perspectives on the aldosterone/MR system

CVD

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.

Effects of Aldosterone in Relation to Sodium Status

Physiologic and Pathophysiologic Effects of Aldosterone on the Kidney and Heart in Relation to Dietary Salt levels

N Engl J Med. 2004;351:8-10.

High

Low

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.

Is aldosterone a cardiovascular risk factor?

Biochimica et Biophysica Acta 1802 (2010) 1188–1192.

Cardiology in Review 2005;13:118–124.

Deleterious actions of Increased MR ActivationIncreased MR

Activation

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.


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

Nature Medicine, Nov 2004

NCX1Ouabain___

N Engl J Med. 2007;356:1966-78.

Ouabain

___

Aldosterone

MR in vascular constriction and

relaxation

In all studies, the effects of Aldo are MR-

dependent, 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.

MR in vascular constriction and relaxation

Molecular and Cellular Endocrinology 350 (2012) 256–265.British Journal of Pharmacology (2011) 163 1163–1169.

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.



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.



When patients with underlying

cardiovascular diseases are studied,

including patients with atherosclerosis,

heart failure, and hypertension, the data

are quite consistent with MR-activation

promoting increased systemic vascular

resistance and reduced forearm blood flow.




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.



MR and Vascular Oxidative Stress

The interaction of ROS with NO also decreases

the bioavailability of NO resulting in impaired

EC-dependent 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.

MR, Aldosterone and Vascular Oxidative Stress

Molecular and Cellular Endocrinology 350 (2012) 256–265.Clinical Science (2007) 113, 267–278.


Molecular and Cellular Endocrinology 350 (2012) 256–265.Clinical Science (2007) 113, 267–278.

peroxinitrite


MR 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

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.

MR, Aldosterone and Vascular Inflammation


MR 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.

MR, Aldosterone and Vascular Remodeling



MR, Aldosterone and Vascular Remodeling

Mineralocorticoid receptors in vascular dysfunction and disease


MR 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

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



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.



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.


MR 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.

MR, Aldosterone and Heart Failure


Curr Heart Fail Rep (2011) 8:7–13.

Characteristics of studies with MR antagonists

Eur J Clin Invest 2012 DOI: 10.1111/j.1365-2362.2012.02676.x

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.

MR, Aldosterone and Heart Failure


MR and 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.

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.



Almost all renal parenchyma are affected

Vasculature

Glomeruli

Tubulointerstitium

Renal vascular changes significantly

contribute Transmural fibrinoid

necrosis

Intimal thickening

Adventitial fibrosis



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

Hypertension 2007;49:355–364.

24h Urinary Protein

Mechanisms of aldosterone/MR-induced kidney injury


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.

MR blockade and Chronic Kidney Disease


MR and the 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.

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.





Aldosterone-releasing factors (ARFs)

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.



Adipocyte


Hypertension 2010;55:813-818.

type 1type 1

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.

Summary - MR and CardioRenal Disease


ΣΑΣ ΕΥΧΑΡΙΣΤΩ

Molecular and Cellular Endocrinology 350 (2012) 273–280.Hypertension 2010;55:813-818.

A hypothetical model of MR pathway activation in type 2 metabolic syndrome (no hyperaldosteronism)

Metabolic syndrome type 2

Documents

ΥΠΟΔΟΧΕΑΣ ΑΛΑΤΟΚΟΡΤΙΚΟΕΙΔΩΝ ΧΑΡΑΚΤΗΡΙΣΤΙΚΑ & ΠΛΕΙΟΤΡΟΠΕΣ ΔΡΑΣΕΙΣ