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menegolo, mirko (2013) Human primary aldosteronism: from clinical observations to in-vivo and ex-vivo studies on the pressor effects of Urotensin II. [Tesi di dottorato]

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Abstract (inglese)

In a patient affected by primary aldosteronism we have identified the presence of a pheochromocytoma not secreting catecholamines. The analysis of the transcriptome in the pheochromocytoma revealed a high expression of Urotensin II (UII).
UII is a somatostatin-like cyclic 11-aminoacid vasoconstrictor peptide, first identified in the teleost fish caudal-neuro-secretory system and then in humans, that has been demonstrated to be a potent vasoactive peptide involved in the physiology and pathophysiology of the cardiovascular system through mechanisms still largely unknown. Its action is now the subject of intensive studies on the effects it produces in different animal models and in different vascular beds. The direct effects on the myocardium such as ventricular hypertrophy, increased extracellular matrix and reduction of myocardial contractility suggest a role of UII in cardiac remodelling after myocardial infarction and heart failure. Even if the effects on cardiovascular system are still controversial UII has attracted considerable scientific interest aimed to investigate on its pathophysiology and on its the mechanism of action.
We investigated among the expression of UII and its receptor in human adrenal glands and in different adrenal tumors. The opposite trend of expression of UII receptor obtained between aldosterone-producing adenoma and pheocromocitoma, along with the differences of genes implicated in UII signaling, supported a role of UII in the paracrine interactions between the adrenal medulla and cortex. Being relevant for the regulation of adrenal gland function and for the pathophysiology of pheocromocitoma and aldosterone-producing adenomas, these interactions might provide a mechanistic explanation for the pheocromocitomas that presented clinically as aldosteronism.
We tested the “in vivo” effects of UII on blood pressure in rats, showing a delayed transient hypertensive effect that resembles the pressure trend in chronic infusion of aldosterone. Thus further supporting the hypothesis of a close interaction between UII and the renin-angiotensin-aldosterone system or even that UII acts through production of aldosterone as well as assess its hypertensive activity, its effect of cardiac hypertrophy and fibrosis and its role in regulating the growth of adrenocortical cells in rats. Considering that the mechanisms involved in the so called “escape phenomenon” seem responsible of the peculiar blood pressure trend in hyperaldosteronism we tested the blood pressure modifications in chronic infusion of UII counteracting the “escape phenomenon” through unilateral nephrectomy, high salt diet and concomitant infusion of spironolactone. The results obtained were promising: for the first time was shown an in-vivo not transient but continuous hypertensive effect of UII.
The evidences obtained in blood pressure modification during chronic infusion of UII combined with the ones regarding UII and development of cortical tumors, has taken a step forward in identifying the mechanism of action of UII supporting the hypothesis of a possible close communication between medulla and adrenal cortex and a possible action of UII mediated by aldosterone. Additional investigations on the transgenic rat overexpressing UII in adrenal medulla will certainly contribute to verify our hypothesis.

Abstract (italiano)

In una paziente affetta da iperaldosteronismo primario abbiamo identificato la presenza di un feocromocitoma non secernente catecolamine. L’analisi del transcrittoma nel feocromocitoma ha rivelato un’elevata espressione di Urotensina II (UII).
L’UII è un peptide ciclico di 11 aminoacidi, identificato inizialmente nel sistema neurosecretorio dei pesci teleostei e successivamente nell’uomo, che oggi è ritenuto un potentissimo vasocostrittore coinvolto nella fisiologia e nella fisiopatologia del sistema cardiovascolare i cui meccanismi di azione sono tuttora largamente sconosciuti. Molti studi su diversi modelli animali, sia in-vitro che in-vivo, hanno documentato che l’UII può indurre ipertrofia cardiaca, aumento della matrice extracellulare e riduzione della contrattilità miocardica, suggerendo una sua possibile implicazione nel rimodellamento cardiaco post-ischemico o nell’insufficienza cardiaca. Nonostante i suoi effetti sul cuore e sull’omeostasi pressoria siano tuttora controversi si è generato un notevole interesse nell’identificazione del ruolo fisiologico dell’UII e dei suoi meccanismi d’azione.
Abbiamo studiato l’espressione dell’UII e del suo recettore nel contesto delle ghiandole surrenaliche e in diversi tumori surrenalici constatando un andamento pressochè opposto circa l’espressione di UII e del suo recettore tra feocromocitoma ed adenoma secernente aldosterone: nel feocromocitoma si è documentato un più alto contenuto di di UII rispetto all’adenoma secernente aldosterone che, viceversa, ha mostrato una maggiore espressione del recettore, suggerendo una down-regulation recettoriale secondaria alla produzione di UII. Queste evidenze suggeriscono un ruolo importante dell’UII nelle interazioni paracrine tra midollare e corticale surrenalica e nella fisiopatologia del pheocromocitoma e dell’adenoma secernente aldosterone, dando peraltro una spiegazione meccanicistica per quei feocromocitomi che si presentano clinicamente con iperaldosteronismo.
Abbiamo inoltre testato in vivo l’effetto dell’UII sulla pressione arteriosa mediante la sua infusione cronica nel ratto documentando un andamento pressorio molto simile a quello che si ottiene nell’infusione cronica di aldosterone e caratterizzato da un iniziale effetto ipertensivo seguito da un adattamento pressorio verso i valori di partenza. Questo supporta ulteriormente l’ipotesi di stretta interazione tra UII e sistema renina-angiotensina-aldosterone o addirittura di un’azione dell’UII mediata dalla produzione di aldosterone. A questo proposito, partendo dal presupposto che il peculiare andamento pressorio negli stati di iperaldosteronismo è pesantemente influenzato dagli adattamenti di volume che si verificano grazie al fenomeno renale di “escape” abbiamo voluto verificare se vi fossero cambiamenti significativi nell’andamento pressorio durante l’infusione cronica di UII e la concomitante soppressione del meccanismo di escape. I risultati sono stati sorprendenti visto che per la prima volta si è documentato in vivo un effetto ipertensivo, non solo transitorio ma continuativo, dell’UII.
Le evidenze ottenute, sia per quel che riguarda gli effetti dell’UII sulla pressione arteriosa che sullo sviluppo dei tumori surrenalici, sicuramente consentono di fare un passo in avanti circa l’identificazione del meccanismo d’azione a sostegno dell’ipotesi che l’UII possa agire come mediatore tra midollare e corticale surrenalica o mediante la produzione stessa di aldosterone. Gli studi in cui prevediamo di utilizzare ratti transgenici per l’espressione di UII nella midollare surrenalica potranno contribuire a confermare o confutare la nostra ipotesi.

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Tipo di EPrint:Tesi di dottorato
Relatore:Rossi, GianPaolo
Correlatore:Grego, franco
Dottorato (corsi e scuole):Ciclo 23 > Corsi per il 23simo ciclo > Ipertensione arteriosa e biologia vascolare
Data di deposito della tesi:28 Gennaio 2013
Anno di Pubblicazione:25 Gennaio 2013
Parole chiave (italiano / inglese):Urotensina II, Iperaldosteronismo primario, ipertensione artriosa Urotensin II, primary aldosteronysm, hypertension
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/11 Malattie dell'apparato cardiovascolare
Struttura di riferimento:Dipartimenti > Dipartimento di Medicina
Codice ID:5507
Depositato il:15 Ott 2013 14:59
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