Expression and functional role of Urotesin-II and its receptor in the adrenal cortex and medulla

Numerous paracrine interactions between the adrenal cortex and medulla are likely to play a role in the pathogenesis of pheochromocytoma (PHEO) and aldosterone-producing adenoma (APA). Nonetheless, the mechanisms underlying excess production of catecholamines in PHEO and of aldosterone in APA are complex and largely unknown. Urotensin II (UII) is a vasoactive peptide that acts through specific G protein-coupled receptor (GPR)-14, named UT-R, and is widely expressed in tissues, including the vasculature and the rat and human adrenal gland. Along with the detection of UII and UT-R gene transcripts in APA and PHEO, these findings led to propose a role of the UII in adrenal gland pathophysiology and, therefore, in the regulation of blood pressure and body fluid homeostasis. However, the quantitative expression of UII and UT-R in APA and PHEO and the biological effects of UII in the adrenal gland remained poorly known. Novel techniques may provide powerful investigative tools to shed new light on the molecular complexity of adrenal tumors. Hence, we used real-time RT-PCR and a whole transcriptome analysis to pinpoint UII and UT-R related pathways in adrenocortical and adreno-medullary tumors and to precisely quantify the UII and UT-R transcripts in APA and PHEO. We next sought for the UII peptide by Western blot analysis and immunohistochemistry. Recently, UT-R antagonists have been prepared and this can enable investigators to directly address the role played by UII and its receptors in different pathophysiological conditions. Moreover, we took advantage of the recent development of palosuran, a specific UT-R antagonist, to investigate the role of UT-R activation on the adrenocortical expression of aldosterone synthase (CYP11B2) and 11? hydroxylase (CYP11B1) by means of a chronic UII infusion on the rat adrenal gland.