Gene Expression and Roles of Angiotensin II Type 1 and Type 2 Receptors in Human Adrenals

Abstract

Although stimulation of aldosterone secretion is one of the functions of angiotensin II, the gene expression and biological significance of the angiotensin II receptor subtypes, AT1 and AT2, in the human adrenal have not been characterized. We therefore investigated the transcription levels of the receptor subtype genes and their roles in regulation of steroid secretion by human adrenals. The expression of AT1 and AT2 receptor mRNA was assessed by reverse transcription-polymerase chain reaction followed by Southern blot analysis in normal adrenocortical tissues (n = 6) and a series of adrenal tumour tissues: aldosterone-producing adrenocortical adenoma (n=6), Cushing's syndrome (n = 6) and pheochromocytoma (n = 6). The role of the two receptor subtypes in steroid secretion in vitro was examined by incubating the tissue with angiotensin II(1 microM) with or without the selective AT1 antagonist CV-11974 (1 microM). Both AT1 and AT2 receptor mRNA transcripts were demonstrated in all of the human adrenal tissues tested. Angiotensin II-induced aldosterone secretion was suppressed 50% upon the addition of CV-11974. The selective AT2 agonist CGP-42112 increased aldosterone secretion by 55% over the control, which was not suppressed by CV-11974. Angiotensin II and CGP-42112 did not affect cortisol secretion. These results suggest that both AT2 and AT1 receptors may be involved in the regulation of aldosterone secretion and tumorigenesis of the human adrenals.

Aldosterone Breakthrough During Angiotensin II Receptor Antagonist Therapy in Stroke-Prone Spontaneously Hypertensive Rats

“…23 In adrenal tissues, both the AT2 receptor and the AT1 receptor are thought to stimulate aldosterone secretion. 5 Although AT1 is the predominant receptor subtype, accounting for 80% of the Ang II receptors in rat and bovine adrenal glands, 24 a contribution of the AT2 receptor could be potentiated if the AT1 receptor is chronically blocked. Therefore, the second potential mechanism of aldosterone breakthrough in our study was that the increased Ang II stimulates aldosterone secretion through the AT2 receptor.…”

“…4 In addition, we have demonstrated that the AT2 receptor may be involved in the stimulation of aldosterone secretion. 5 Selective antagonism of the AT1 receptor is known to be associated with a substantial increase in plasma Ang II levels. 6 It is therefore suggested that the increased plasma Ang II may stimulate aldosterone secretion through the AT2 receptor with the AT1 receptor blocked.…”

Immunohistochemical detection of angiotensin receptors AT1 and AT2 in adrenal tumors.

“…This observation is compatible with some data from earlier papers. Tanabe et al [8] and Kitamura et al [12] reported on the expression of AT1 mRNAs in both aldosterone-and cortisol-secreting adenomas. Opocher et al [11] studied the binding of labeled Ang II in presence or absence of specific receptor blockers concluded that Ang II receptors are present in both aldosterone-sereting and cortisol-secreting adenomas, but in the latter the receptor density is lower than in the normal adrenal tissue.…”

“…Although the adrenal gland is affected by circulating Ang II, the peptide can be also generated within the gland by a local reninangiotensin system [4,5]. Both main subtypes of Ang II receptors, AT1 and AT2 were identified in rodent and human adrenal cortex and medulla [6][7][8]. In adrenal cortex, AT1 subtype is prevalent, whereas in adrenal medulla the AT2 subtype dominates [6].…”

PET Imaging of the AT1 receptor with [11C]KR31173

“…Dogs, baboons, and probably pigs can be used as animal models for human AT 1 R imaging since, in contrast to rodents in which two subtypes, AT 1a and AT 1b , have been discovered, dogs, baboons and pigs, like humans, possess only one subtype of these receptors, i.e., AT 1 R. The PET images showed high [ 11 C]KR31173 binding in the adrenal glands of dogs and a baboon, confirming the ex vivo binding studies performed in mice. The adrenals have a very high density of the AT 1 R which also undergoes hormonal regulation [7,29] and is involved in the regulation of the biosynthesis and secretion of aldosterone [30][31][32][33]. Of potential interest for imaging studies is the application of AT 1 R PET in aldosterone producing tumors.…”