The Effects of the Endothelium on Adrenal Steroidogenesis and Growth are Mainly Mediated by Proteins Other than Endothelin-1

Abstract

The endothelium releases factors stimulating the adrenal cortex. It is also known that endothelin-1 (ET-1) promotes generation of cortisol and aldosterone, and proliferation of adrenocortical cells. The aim of the study was to find out whether the effect of the endothelium on adrenocortical cells is dominated by the action of ET-1. The effects of endothelial cell-conditioned medium (ECCM), obtained during growth of human umbilical cord vein endothelial cells, on aldosterone and cortisol release by cells of the adrenocortical cancer cell-line NCI-H295R and the promoter activity of steroidogenic acute-regulatory protein (StAR) were studied. The effect of ECCM on proliferation of human primary normal adrenocortical and NCI-H295R cells was also investigated. Concentration-dependent increases in cortisol release that reached 192.7 ± 62.8 in percent of basal secretion, in aldosterone release that reached 188.2 ± 52.3 in percent of basal secretion, and in proliferation after stimulation with ECCM at concentrations of 10-50% were found. ECCM significantly activated the StAR promoter 3-fold in NCI-H295R cells if the ECCM was not pretreated with pronase. These effects of the endothelium were not reversed after co-incubation with endothelin receptor antagonists and could not be mimicked by incubation with endothelin-1. In conclusion, the cultured endothelial cells secrete a protein that stimulates steroidogenesis in adrenal cells and their growth. It was also shown that the ET-1 does not mediate the effect of ECCM on the NCI-H295R cell line.

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“…ACTH and cortisol serum concentrations were measured by radioimmunoassays (Diagnostic System Laboratories Deutschland DSL, Sinsheim, Germany) as recently described [26]. Concentrations are given as pg/ml for ACTH and μg/dl for cortisol.…”

Endothelial dysfunction: a critical determinant in inflammation-associated adrenal insufficiency?

“…In addition, endothelial cell–derived factors may synergize with angiotensin II in aldosterone induction or even sensitize mineralocorticoid cells to angiotensin II stimulation [13]. Moreover, endothelial cell–conditioned medium can stimulate proliferation of human primary normal adrenocortical and of the adrenocortical cancer cell line NCI‐H295R [14].…”

“…For example, endothelial cell‐conditioned media are capable of stimulating the expression of aldosterone synthase as well as the promoter activity of steroidogenic acute‐regulatory protein (StAR) and thereby steroidogenesis stimulating both aldosterone and cortisol release. These endothelial effects may be in parts because of the actions of endothelial‐derived factors, such as nitric oxide or endothelin [10–14]. In addition, endothelial cell–derived factors may synergize with angiotensin II in aldosterone induction or even sensitize mineralocorticoid cells to angiotensin II stimulation [13].…”

Effect of Bosentan and Losartan on Oxidative Stress and Cortisol level in Endothelin-1 and Angiotensin II Treated Rats

“…However, the current result agree with (Ansurudeen et al 2014) demonstrated that Ang II causes an increase in cortisol production. (Paramonova et al 2010) reported that ET-1 causes proliferation of adrenocortical cells and promotes cortisol secretion. Furthermore, hypercortisolemia has related with elevated ET-1 levels (Lederbogen et al 1999).…”