Expression of vasopressin receptors in ACTH-independent macronodular bilateral adrenal hyperplasia causing Cushing's syndrome: molecular, immunohistochemical and pharmacological correlates

Abstract

Cortisol secretion in ACTH-independent macronodular adrenal hyperplasia (AIMAH) causing Cushing's syndrome can be controlled by illegitimate receptors. The aim of the present study was to characterize the molecular, immunohistochemical, and pharmacological profiles of vasopressin receptors in cells derived from three patients with AIMAH (H1-H3), in order to evaluate the role of ectopic vasopressin receptors in the physiopathology of hypercortisolism. Expression of mRNAs encoding the vasopressin receptor types (V 1a , V 1b , and V 2 ) were analyzed by RT-PCR in adrenal tissues. The presence of V 1a and V 2 receptors was studied by immunohistochemistry on adrenal sections. The pharmacological profiles of vasopressin receptors involved in the control of cortisol secretion were investigated using the V 1a receptor antagonist SR49059 and the V 2 receptor agonist [deamino-Cys ]-vasopressin on cultured cells. The V 1a receptor protein was present and functional in H1 and H3 tissues, whereas the V 1b receptor was not expressed in any of the tissues. RT-PCR experiments revealed that V 2 receptor mRNAs were detected in the three tissues. In contrast, immunohistochemical and cell incubation studies showed that the V 2 receptor was involved in the stimulatory effect of AVP on cortisol secretion in H1 and H2, but not in H3 cells. Taken together, these data show that expression of functional ectopic V 2 receptors and repression of eutopic V 1a receptor can coexist in some hyperplastic corticosteroidogenic tissues. They also reveal that immunohistochemical and incubation studies are essential for the characterization of ectopic receptors actually involved in the control of cortisol secretion by AIMAHs.

Aberrant cortisol regulations in bilateral macronodular adrenal hyperplasia: a frequent finding in a prospective study of 32 patients with overt or subclinical Cushing's syndrome

“…Systematic in vitro characterization of the different receptors involved was not possible because most of the patients had SCS and were not operated on. For some operated patients, studies were conducted to correlate the in vivo responses with in vitro data (previously published in (6,14,18,32)). Aberrant expression of the GIP receptor in AIMAH tissues was confirmed in the three food-dependent CS patients.…”

Screening for membrane hormone receptor expression in primary aldosteronism

“…The effects of vasopressin on cortisol (33) and short term aldosterone release are well established (34) and V1aR are present in normal adrenal tissue, in cortisol-producing adrenal adenomas, AIMAH as well as in aldosteronomas (19,24,35). In addition, AVP stimulates central ACTH secretion (36), which in turn can modulate aldosterone release.…”

“…Furthermore, the overexpression of eutopic receptors could be linked to cortisol production in several cases. Specifically, receptors for angiotensin II (16), vasopressin (17)(18)(19), and serotonin (20,21) could be shown to be involved in the pathogenesis of autonomous cortisol secretion.…”

Multiple aberrant hormone receptors in Cushing's syndrome

“…Paracrine regulatory mechanisms of cortisol secretion were proposed following the demonstration of increased adrenocortical expression of pro-opiomelanocortin (POM-C)/ACTH, serotonin, vasopressin or glucagon in some affected adrenal tissues (53,72,84,85,86,87). A complex paracrine regulation was confirmed by the recent demonstration of expression of POMC in clusters of steroidogenic cells in the majority of 30 tissues studied from patients with BMAH and CS (34).…”