Endothelin-1[1–31], acting as an ETA-receptor selective agonist, stimulates proliferation of cultured rat zona glomerulosa cells

AbstractEndothelin-1 (ET-1)[1–31] is a novel hypertensive peptide that mimics many of the vascular effects of the classic 21 amino acid peptide ET-1[1–21]. However, at variance with ET-1[1–21] that enhances aldosterone secretion from cultured rat zona glomerulosa (ZG) cells by acting via ETB receptors, ET-1[1–31] did not elicit such effect. Both ET-1[1–21] and ET-1[1–31] raised the proliferation rate of cultured ZG cells, the maximal effective concentration being 10−8 M. This effect was blocked by the ETA-receptor antagonist BQ-123 and unaffected by the ETB-receptor antagonist BQ-788. Quantitative autoradiography showed that ET-1[1–21] displaced both [125I]PD-151242 binding to ETA receptors and [125I]BQ-3020 binding to ETB receptors in both rat ZG and adrenal medulla, while ET-1[1–31] displaced only [125I]BQ-3020 binding. The tyrosine kinase (TK) inhibitor tyrphostin-23 and the p42/p44 mitogen-activated protein kinase (MAPK) inhibitor PD-98059 abolished the proliferogenic effect of ET-1[1–31], while the protein kinase-C (PKC) inhibitor calphostin-C significantly reduced it. ET-1[1–31] (10−8 M) stimulated TK and MAPK activity of dispersed ZG cells, an effect that was blocked by BQ-123. The stimulatory action of ET-1[1–31] on TK activity was annulled by tyrphostin-23, while that on MAPK activity was reduced by calphostin-C and abolished by either tyrphostin-23 and PD-98059. These data suggest that ET-1[1–31] is a selective agonist of the ETA-receptor subtype, and enhances proliferation of cultured rat ZG cells through the PKC- and TK-dependent activation of p42/p44 MAPK cascade

Endothelin-1 [1-311 acts as a selective ETA-receptor agonist in the rat adrenal cortex

Endothelin-1 (ET-1) is a 21-amino acid residue (ET-1[1-211) hypertensive peptide, which together with its receptor subtypes A and B (ETA and ETB) is expressed in the rat adrenal cortex, where it stimulates steroid-hormone (aldosterone and corticosterone) secretion through the ETB receptor and the growth (proliferative activity) of the zona glomerulosa (ZG) through the ETA receptor. ET-1[1-211 is generated from bigET-1 by the endothelin-converting enzyme (ECE-1). However, recent evidence indicates the existence of an alternative chymase-mediated biosynthetic pathway leading to the production of an ET- 1[1-311 peptide, which was found to reproduce the ETA receptor-mediated vascular effects of ET-l[l-211. We found that ET-1[1-211, but not ET-1[1-311, concentration-dependently raised steroid secretion from dispersed rat adrenocortical cells, its effect being blocked by the ETB-receptor selective antagonist BQ- 788. Both ET-1s concentration-dependently increased the number of "S-phase" cells (as detected by the 5- bromo-2'-deoxyuridine immunocytochemical method) in capsule-ZG strips within a 240 min incubation. The ZG proliferogenic action of both ET-1s was blocked by the ETA-receptor antagonist BQ-123, and ET-l[l-311 was found to be significantly more potent than ET-1[1- 211. Autoradiography showed that in the rat adrenal ET- 1[1-211 displaced the binding of selective ligands to both ETA ([125I]PD-151242) and ETB receptors ([125I]BQ-3020), while ET-l[l-311 eliminates only the binding to ETA receptors. Collectively, our findings provide strong evidence that ET-1[1-311 acts in the rat adrenal glands as a selective ETA-receptor agonist, mainly involved in the stimulation of ZG proliferative activity

Tissue culture of rat adult decapsulated adrenal glands. A methodological, ultrastructural and morphometric investigation

The primary tissue culture of rat adult decapsulated adrenal gland cells: a methodological, ultrastructural and morphometric investigatio

Electron microscopy of primary tissue culture of adult human adrenal gland.

The ultrastructural differentiative changes elicited by the treatment with ACTH(1-24) in primary normal human adullt adrenocortical cells are reported for the first tim

proadrenomedullin-derived peptides as autocrine-paracrine regulators of cell growth

Proadrenomedullin (pADM)-derived peptides, adrenomedullin (ADM) and pADM N-terminal 20 peptide (PAMP), are hypotensive peptides, which are expressed, along with their receptors, in several tissues and organs, the function of which they regulate by acting in an autocrine-paracrine manner. Apart from their involvement in the regulation of blood pressure and fluid and electrolyte homeostasis, pADM-derived peptides appear to play a role in the modulation of cell and tissue growth. Evidence has been provided that ADM: 1) favors the remodeling of cardiovascular system under pathological conditions, by exerting an antiapoptotic effect on endothelial cells and an antiproliferogenic and antimigratory action on vascular smooth-muscle cells during neointimal hyperplasia, and by decreasing proliferation and protein synthesis of cardiac myocytes and fibroblasts. These last two effects are mediated by calcitonin gene-related peptide type 1 (CGRPl) receptors coupled to the adenylate cyclase (AC)/protein kinase (PK) A-dependent cascade; 2) inhibits proliferation and enhances apoptosis of kidney mesangial cells, through the modulation of mitogenactivated PK (MAPK) cascades; 3) stimulates proliferation of adrenal zona glomerulosa cells, acting via CGRPl receptor coupled to the tyrosine kinasedependent MAPK cascade, thereby possibly being involved in the maintenance and stimulation of adrenal growth; 4) enhances proliferation of skin and mucosa epithelia1 cells and fibroblasts, by activating CGRPl receptor coupled to the ACIPKA signaling pathway; and 5) enhances proliferation of several tumor-cell lines through the activation of the ACIPKA cascade, which suggests a potential role for ADM as promoter of neoplastic growth. The growth effects of PAMP have been far less investigated: findings indicate that this peptide, like ADM, enhances adrenal zona glomerulosacell proliferation, and, in contrast with ADM, depresses DNA synthesis in some cancer-cell lines. Both pADMderived peptides are thought to be involved in embryogenesis, such a contention being based on the demonstration of high pADM-gene expression during the crucial phases of organ growth and differentiation

Paracrine control of steroid hormone secretion by chromaffin cells in the adrenal gland of lower vertebrates

The adrenal glands of lowe r vertebrates display a notable intermingling between steroidogenic and chromaffin tissues, which increases from Pisces to Al'es. As in mammals, adrenal chromaffin cells contain and release, in addition to catechol amines, serotonin and several peptides, which may affect the secretory acti vity of steroidogeni c cells in a paracrine manner. Stimulatory molec ul es in c lud e se roto nin , arg inin e-va so tocin. tachykinin s, vasoac ti ve intestinal peptide , pituita ry adenylate cyclase-acti vating peptide and calcitonin generelated peptide: inhibitory molec ul es are dopamine, somatotropic hormone-release inhibiting hormone and ga lanin . Epin ephrine and no repinephrine appe ar to stimulate steroid sec retion in Aves and to inhibit it in Pisces, while their ac tion in Amphibia is controversial. Likewise . atri a l natriureti c peptide exe rts an antisec re ta gog ue ac ti o n in Amphibia and a ma rk ed secretagogue effe ct in Pisces and Aves. The effects of opioids (enkephalins and endorphins) have scarcely been in vesti ga ted a nd th e findin gs obt a ined a re hi g hly qu esti o nabl e. Compared with the ama zin g ma ss of in vestigations carried out in mammals, studies in lower ve rtebrates a re few, and in large part pe rformed in Amphibia and Al'es. It appears that much further work has to be done by comparati ve endocrinologists to fully clari fy the physiolog ica l relevance of th e functi onal interactions between chromaffin and steroidogeni c cells in the adrenal glands of lower vertebrates