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Expression and Functional Role of Urotensin-II and Its Receptor in the Adrenal Cortex and Medulla: Novel Insights for the Pathophysiology of Primary Aldosteronism

Departments of Clinical and Experimental Medicine (Department of Clinical and Experimental Medicine-Internal Medicine 4) (L.G., L.L., E.A., G.P.R.), Vascular Surgery (M.A.), Human Anatomy and Physiology (Section of Anatomy) (A.S.B.), and Chair of Pathology (A.F.), School of Medicine, University of Padua, I-35121 Padua, Italy; and Division of Endocrinology (C.G.-S.), G. V. (Sonny) Montgomery Veterans Affairs Medical Center, and Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi 39216

Address all correspondence and requests for reprints to: Prof. Gian Paolo Rossi, M.D., FACC, FAHA, Department of Clinical and Experimental Medicine, Internal Medicine 4, University Hospital, via Giustiniani, 2, 35126 Padova, Italy. E-mail: gianpaolo.rossi{at}unipd.it.

Context: The involvement of urotensin II, a vasoactive peptide acting via the G protein-coupled urotensin II receptor, in arterial hypertension remains contentious.

Objective: We investigated the expression of urotensin II and urotensin II receptor in adrenocortical and adrenomedullary tumors and the functional effects of urotensin II receptor activation.

Design: The expression of urotensin II and urotensin II receptor was measured by real time RT-PCR in aldosterone-producing adenoma (n = 22) and pheochromocytoma (n = 10), using histologically normal adrenocortical (n = 6) and normal adrenomedullary (n = 5) tissue as control. Urotensin II peptide and urotensin II receptor protein were investigated with immunohistochemistry and immunoblotting. To identify urotensin II-related and urotensin II receptor-related pathways, a whole transcriptome analysis was used. The adrenocortical effects of urotensin II receptor activation were also assessed by urotensin II infusion with/without the urotensin II receptor antagonist palosuran in rats.

Results: Urotensin II was more expressed in pheochromocytoma than in aldosterone-producing adenoma tissue; the opposite was seen for the urotensin II receptor expression. Urotensin II receptor activation in vivo in rats enhanced (by 182 ± 9%; P < 0.007) the adrenocortical expression of immunoreactive aldosterone synthase.

Conclusions: Urotensin II is a putative mediator of the effects of the adrenal medulla and pheochromocytoma on the adrenocortical zona glomerulosa. This pathophysiological link might account for the reported causal relationship between pheochromocytoma and primary aldosteronism.