Eutopic Overexpression of Vasopressin V_1aReceptor in Adrenocorticotropin-Independent Macronodular Adrenal Hyperplasia

Abstract

Arginine vasopressin (AVP) stimulates cortisol secretion through its vascular type V(1a) receptor in the adrenal glands, in addition to stimulating ACTH secretion through pituitary V(3) receptor. Because hyper-response of plasma cortisol to vasopressin is documented in some patients with Cushing's syndrome due to adrenal adenoma (CS) or ACTH-independent macronodular adrenocortical hyperplasia (AIMAH), we analyzed the expression of V(1a), V(2), V(3) receptor and AVP mRNA in human adrenal tissues by quantitative competitive RT-PCR or real-time PCRs. V(1a) receptor mRNA levels (ratio against glyceraldehyde 3-phosphate dehydrogenase) were 0.378 +/- 0.143 (mean +/- SE) in preclinical CS (n = 5) and 0.630 +/- 0.072 in AIMAH (n = 4), which were significantly higher than those (0.046 +/- 0.012; n = 9) in control adrenals, whereas those in overt CS (0.143 +/- 0.048; n = 10) or aldosterone-producing adenomas (0.069 +/- 0.018; n = 12) were similar to control adrenals. Although ectopic expression of V(2) or V(3) receptor was detected in half of AIMAH cases, the absolute levels were low. Furthermore, V(1a) receptor mRNA levels in the adjacent adrenal glands (0.190 +/- 0.039, n = 9) of aldosterone-producing adenomas were higher than those in control adrenals and in the corresponding tumor portions (0.079 +/- 0.024). In contrast, there were no significant differences in AVP mRNA levels among these groups. These results suggest that eutopic V(1a) receptor overexpression is involved in the etiology of AIMAH and a subset of adrenal adenomas causing overt or preclinical Cushing's syndrome. Our results imply a possible association of V(1a) receptor expression with adrenal hyperplasia.

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

“…Expression of the V 1b receptor gene has been shown in some AIMAH tissues (Mune et al 2002, Miyamura et al 2003, Lee et al 2005. The fact that V 1b receptor mRNA cannot be detected in present RT-PCR experiments excludes the involvement of ectopic V 1b receptors in AVP-induced cortisol production in the three AIMAH tissues.…”

“…It was conceivable that hypersensitivity of cortisol secretion to AVP in these patients might result from activation of illegitimate receptors, i.e., overexpressed eutopic V 1a receptors and/or ectopic V 1b and V 2 receptors. In agreement with this hypothesis, molecular studies have shown overexpression of V 1a receptor and abnormal expression of V 1b and V 2 receptor mRNAs in whole tissue explants removed from AIMAHs (Miyamura et al 2002, Mune et al 2002, Lee et al 2005. However, RT-PCR data are ambiguous since it has been reported that adrenal chromaffin cells and blood vessels express the V 1b and V 2 receptors respectively (Aldasoro et al 1997, Grazzini et al 1999, Medina et al 1999.…”

MECHANISMS IN ENDOCRINOLOGY: Autocrine/paracrine regulatory mechanisms in adrenocortical neoplasms responsible for primary adrenal hypercorticism

“…Abnormal adrenal sensitivity to AVP has been shown in patients who displayed high plasma cortisol responses to injection of AVP or physiological tests modifying plasma AVP levels (water or hypertonic saline absorption) (122,123,124), and exaggerated cortisol responses of adrenocortical cells to AVP have been observed in vitro (95,97,119,120,123). The increased sensitivity of adrenocortical cells to AVP has been ascribed to overexpression of the eutopic V1a receptor subtype (120,125,126,127) and/or expression of ectopic V1b and V2 receptors (127,128,129). Similarly, mRNAs encoding the V1a and V2 receptors have been detected at variable levels in aldosteroneproducing adenomas (61,130,131).…”

Cushing's syndrome secondary to ACTH-Independent macronodular adrenal hyperplasia

“…However, ACTH-independent stimulation of cortisol following administration or arginine-or lysine-vasopressin has been reported in several patients with either unilateral adenoma or AIMAH and CS who increase their plasma cortisol with upright posture and other physiological stimuli of endogenous vasopressin (2,(42)(43)(44)(45)(46)(47). As pharmacological levels of AVP can stimulate catecholamine secretion and cortisol production indirectly in patients with ectopic adrenal β-adrenergic receptors, it is important to demonstrate that the cortisol production is modulated by endogenous vasopressin through water and hypertonic sodium loading (42,44).…”

“…The V1-vasopressin receptor is normally expressed in the adrenal cortex and stimulates steroidogenesis modestly in vitro, but this is not detectable in vivo; because of this, it has been proposed that the exaggerated steroidogenic response in these patients represents an increased response via an eutopic receptor, as a result of receptor over-expression and/or more efficient receptor coupling to intracellular steroidogenic pathways (2,45,46). Recently, ectopic expression of V2-and V3-vasopressin receptors was reported in vitro in some AIMAH cases, but the effect of dDAVP, a preferential agonist of V2 receptors, was not studied or did not elicit cortisol response in vivo (47,48).…”