Localization of the Endothelin System in Aldosterone-Producing Adenomas

Abstract

Abstract-Endothelin-1 (ET-1) could play a role in the regulation of aldosterone secretion of the human adrenal gland. The presence of the endothelin-converting enzyme 1 (ECE-1) and ET-1 suggests that there is a local ET system in the adrenal cortex, but the in situ synthesis of ET-1 remains to be confirmed. The cellular distribution of the whole ET system was evaluated in 20 cases of aldosterone-producing adenomas. Polymerase chain reaction studies gave strong signals for ECE-1 mRNA and the mRNAs for endothelin type A (ET A ) and B (ET B ) receptors and faint signals for prepro-ET-1 mRNA. In situ hybridization showed ET A receptors scattered throughout the adenoma, in both secretory cells and vascular structures (score, ϩ). There were more ET B receptors (score, ϩϩ), but they were restricted mainly to the endothelium. ECE-1 mRNA and protein were ubiquitous and abundant in secretory cells (score, ϩϩϩ) and vascular structures (score, ϩϩ); the enzyme was active on big ET-1. There was no prepro-ET-1 mRNA in the cortex, except in the thickened precapillary arterioles present in only 30% of the aldosterone-producing adenomas studied. ET-1 immunoreactivity was detected in vascular structures (score, ϩ), probably bound to receptors, suggesting that ET-1 has an endocrine action. The low concentrations of ET-1 could also indicate that it acts in a paracrine-autocrine fashion to control adrenal blood flow. The discrepancy between the concentrations of ECE-1 and its substrate suggests that ECE-1 has another role in the adrenal secretory cells. Our data indicate that ET probably is not a primary cause of the development or maintenance of the adenoma. Key Words: endothelin Ⅲ hypertension, endocrine Ⅲ receptors, endothelin Ⅲ regional blood flow Ⅲ immunohistochemistry E ndothelin-1 (ET-1) is one of three 21-amino acid peptides, the ETs (ET-1, ET-2, and ET-3), that mediate a broad spectrum of biologic actions, such as the regulation of endocrine secretion. 1 It also is involved in specific vascular lesions and inflammatory conditions (primary and malignant hypertension). 2 The ETs act on 2 distinct high-affinity G protein-coupled receptors, endothelin type A (ET A ) 3 and type B (ET B ), 4 and are synthesized as large precursor polypeptides, the prepro-ETs, which are cleaved at 2 pairs of basic amino acids to generate intermediate peptides, the big ETs. The big ETs are then cleaved by an endothelin-converting enzyme (ECE), initially purified from bovine adrenal cortex, 5 to produce the mature ETs. Two human ECE genes have been cloned, ECE-1 6 and ECE-2, 7 and they are 59% identical.ET-1 was first found in the vascular endothelium, 8 but it is also present in endocrine tissues, such as the adrenal gland, 9 where it may mediate the adrenocortical response to ACTH. 10 Large amounts of ECE-1 mRNA and protein have been found in the human adrenal gland, with the highest concentrations in the zona glomerulosa and fasciculata. 11 Both ET receptor subtypes and ET peptides are found in the human adrenal gland. 9 The mRNAs for ET A , ET B ...

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

“…Gene expression of the complete endothelin system was confirmed by microarray analysis, at levels equivalent to those of normal adrenal (178). In situ hybridization experiments have localized prepro-ET-1, ECE, and ETA and ETB receptor mRNAs in vascular structures (177). They have also revealed the presence of ECE and ETA receptor transcripts in steroidogenic adenoma cells (177).…”

“…The occurrence and role of endothelin system in the control of steroidogenesis have been extensively investigated in adrenal lesions associated with hyperaldosteronism. Expression of genes encoding prepro-ET-1, ECE-1, and ETA and ETB receptors has been detected in aldosterone-producing adenomas by PCR (177). Gene expression of the complete endothelin system was confirmed by microarray analysis, at levels equivalent to those of normal adrenal (178).…”

“…In situ hybridization experiments have localized prepro-ET-1, ECE, and ETA and ETB receptor mRNAs in vascular structures (177). They have also revealed the presence of ECE and ETA receptor transcripts in steroidogenic adenoma cells (177). In addition, it is now clear that genes encoding the different components of the endothelin system are translated into proteins.…”

À quoi sert le système endothéline ?

“…Une très forte expression a été observée dans la surrénale [6]. La pré-sence d'ET-1 dans les structures vasculaires suggère une action autocrine et/ou paracrine sur le contrôle du flux sanguin dans la surrénale [13]. Les concentrations extrêmement élevées d'ECE-1 font penser que d'autres substrats que la big ET-1 sont clivés.…”

Adrenal endothelin-1 levels are not associated with aldosterone secretion in primary aldosteronism

“…Recent studies have also shown that aldosterone can, in turn, upregulate ET-1 expression (13)(14)(15). Since normal adrenal tissue and adrenal adenomas express components of the ET system (16)(17)(18), a positive feedback loop between ETs and aldosterone may be hypothesized. Moreover, any ET spillover from the adrenal gland may have pathophysiological and diagnostic implications.…”