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ΥΠΟΔΟΧΕΑΣ ΑΛΑΤΟΚΟΡΤΙΚΟΕΙΔΩΝ ΧΑΡΑΚΤΗΡΙΣΤΙΚΑ & ΠΛΕΙΟΤΡΟΠΕΣ ΔΡΑΣΕΙΣ Κωνσταντίνος Π. Μακαρίτσης Παθολογική Κλινική Πανεπιστημίου Θεσσαλίας 23 Ιανουαρίου 2014.

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Παρουσίαση με θέμα: "ΥΠΟΔΟΧΕΑΣ ΑΛΑΤΟΚΟΡΤΙΚΟΕΙΔΩΝ ΧΑΡΑΚΤΗΡΙΣΤΙΚΑ & ΠΛΕΙΟΤΡΟΠΕΣ ΔΡΑΣΕΙΣ Κωνσταντίνος Π. Μακαρίτσης Παθολογική Κλινική Πανεπιστημίου Θεσσαλίας 23 Ιανουαρίου 2014."— Μεταγράφημα παρουσίασης:

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2 ΥΠΟΔΟΧΕΑΣ ΑΛΑΤΟΚΟΡΤΙΚΟΕΙΔΩΝ ΧΑΡΑΚΤΗΡΙΣΤΙΚΑ & ΠΛΕΙΟΤΡΟΠΕΣ ΔΡΑΣΕΙΣ Κωνσταντίνος Π. Μακαρίτσης Παθολογική Κλινική Πανεπιστημίου Θεσσαλίας 23 Ιανουαρίου 2014

3 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

4 ENaC NCCT NKCC2 NHEs N Engl J Med Aldosterone

5 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.

6 Aldosterone-Regulated Transport - Cortical Collecting Tubule

7 Amiloride Triamterene Spironolactone Eplerenone X X N Engl J Med 1999;340:

8 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.

9 Regulation of ENaC membrane expression Insulin MR α β γ

10 Mineralocorticoid Receptor-MR Στοιχεία Παθοφυσιολογίας

11 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 φορές υψηλότερα από τα επίπεδα της αλδοστερόνης. Στοιχεία Παθοφυσιολογίας

12 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:

13 Aldosterone signaling Hypertension. 2011;57: Rapid non-Genomic Effects Genomic Effects PI3K

14 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)

15 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 φορές υψηλότερα από τα επίπεδα της αλδοστερόνης;;; Mineralocorticoid Receptor-MR Molecular and Cellular Endocrinology 350 (2012) 289–298.

16 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. Mineralocorticoid Receptor-MR Molecular and Cellular Endocrinology 350 (2012) 289–298.

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18 11β-HSD2 * * 11β-Hydroxy Steroid Dehydrogenase2 SAME Syndrome Glycyrrhizic acid Carvenoxolone Congenital Adrenal Hyperplasia CHIMERIC GENE GRA

19 Hypertens Res 2004; 27: 781–789. Mineralocorticoid Receptor-MR

20 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.

21 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.

22 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:

23 Clin Exp Nephrol (2010) 14:303–314. Phylogenetic perspectives on the aldosterone/MR system CVD

24 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

25 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

26 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.

27 Cardiology in Review 2005;13:118–124. Deleterious actions of Increased MR Activation Increased MR Activation

28 MR, Aldosterone and Blood Pressure

29 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

30 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

31 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. MR, Aldosterone and blood pressure

32 Pathways of salt-sensitive hypertension Nature Medicine, Nov 2004 NCX1 Ouabain ___

33 N Engl J Med. 2007;356: Ouabain ___ Aldosterone

34 MR in vascular constriction and relaxation

35 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) –1169.

36 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. MR in vascular constriction and relaxation Molecular and Cellular Endocrinology 350 (2012) 256–265. British Journal of Pharmacology (2011) –1169.

37 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. MR in vascular constriction and relaxation Molecular and Cellular Endocrinology 350 (2012) 256–265. British Journal of Pharmacology (2011) –1169.

38 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. MR in vascular constriction and relaxation Molecular and Cellular Endocrinology 350 (2012) 256–265. British Journal of Pharmacology (2011) –1169.

39 MR in vascular constriction and relaxation

40 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 in vascular constriction and relaxation Molecular and Cellular Endocrinology 350 (2012) 256–265. British Journal of Pharmacology (2011) –1169.

41 MR and Vascular Oxidative Stress

42 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.

43 MR, Aldosterone and Vascular Oxidative Stress Molecular and Cellular Endocrinology 350 (2012) 256–265. Clinical Science (2007) 113, 267–278. peroxinitrite

44 MR, Aldosterone and Vascular Oxidative Stress

45 MR and Vascular Inflammation

46 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 Molecular and Cellular Endocrinology 350 (2012) 256–265.

47 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 Molecular and Cellular Endocrinology 350 (2012) 256–265.

48 MR and Vascular Remodeling

49 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 Molecular and Cellular Endocrinology 350 (2012) 256–265.

50 MR, Aldosterone and Vascular Remodeling

51 Mineralocorticoid receptors in vascular dysfunction and disease Molecular and Cellular Endocrinology 350 (2012) 256–265.

52 MR and Myocardial Remodeling

53 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 Molecular and Cellular Endocrinology 350 (2012) 248–255.

54 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 MR, Aldosterone and Myocardial Remodeling Molecular and Cellular Endocrinology 350 (2012) 248–255.

55 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. MR, Aldosterone and Myocardial Remodeling Molecular and Cellular Endocrinology 350 (2012) 248–255.

56 Aldosterone effect on the expression of profibrotic factors Clinical Science (2007) 113, 267–278.

57 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.

58 MR and Heart Failure

59 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 Molecular and Cellular Endocrinology 350 (2012) 266–272.

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61 Curr Heart Fail Rep (2011) 8:7–13. Characteristics of studies with MR antagonists

62 Eur J Clin Invest 2012 DOI: /j x

63 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= ) 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 Molecular and Cellular Endocrinology 350 (2012) 266–272.

64 MR and Kidney Disease

65 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 Molecular and Cellular Endocrinology 350 (2012) 273–280.

66 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. MR, Aldosterone and Chronic Kidney Disease Molecular and Cellular Endocrinology 350 (2012) 273–280.

67 Almost all renal parenchyma are affected Vasculature Glomeruli Tubulointerstitium Renal vascular changes significantly contribute Transmural fibrinoid necrosis Intimal thickening Adventitial fibrosis MR, Aldosterone and Chronic Kidney Disease Molecular and Cellular Endocrinology 350 (2012) 273–280.

68 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. MR, Aldosterone and Chronic Kidney Disease Molecular and Cellular Endocrinology 350 (2012) 273–280. Hypertension 2007;49:355–364.

69 Involvement of podocyte damage in the renal dysfunction of aldosterone/salt-treated rats Hypertension 2007;49:355– h Urinary Protein

70 Mechanisms of aldosterone/MR-induced kidney injury Molecular and Cellular Endocrinology 350 (2012) 273–280.

71 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 Molecular and Cellular Endocrinology 350 (2012) 273–280.

72 MR and the Metabolic Syndrome

73 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 Molecular and Cellular Endocrinology 350 (2012) 273–280.

74 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. MR, Aldosterone and Metabolic Syndrome Molecular and Cellular Endocrinology 350 (2012) 273–280.

75 Molecular and Cellular Endocrinology 350 (2012) 281–288. MR, Aldosterone and Metabolic Syndrome Aldosterone-releasing factors (ARFs)

76 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. MR, Aldosterone and Metabolic Syndrome Molecular and Cellular Endocrinology 350 (2012) 273–280.

77 Adipocyte MR, Aldosterone and Metabolic Syndrome Hypertension 2010;55: type 1

78 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 Molecular and Cellular Endocrinology 350 (2012) 266–272.

79 ΣΑΣ ΕΥΧΑΡΙΣΤΩ

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81 Molecular and Cellular Endocrinology 350 (2012) 273–280. Hypertension 2010;55: A hypothetical model of MR pathway activation in type 2 metabolic syndrome (no hyperaldosteronism) Metabolic syndrome type 2


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