The mineralocorticoid hormone aldosterone is secreted by the adrenal cortex. It plays a major role in maintaining water and electrolyte balance and hence blood pressure homeostasis by the kidneys. The aldosterone synthesizing zona glomerulosa of the adrenal cortex is a highly vascularized region. This allows a complex and articulated interaction between the steroidogenic cells and the vascular endothelial cells regulating the hormonal output.
In this study we show that coculture of human adrenocortical cells (NCI-H295R) with freshly isolated human umbilical vein endothelial cells (HUVECs) over 24 h increased the aldosterone production in NCI-H295R cells. This stimulation reached 70 to 80% of angiotensin II (100 nM) or forskolin (20 μM) induced stimulation of aldosterone secretion. A similar effect was observed with 24 h HUVEC-conditioned media (HCM).
HCM-induced stimulation of aldosterone production was accompanied by a 3040% increased phosphorylation of cyclic-AMP response element (CREB). The increase in aldosterone secretion was not affected by either the Protein kinase A (PKA) inhibitor H89 (10 μM), or by pertussis toxin (200 ng/ml), interacting with Gi proteins. Further studies with inhibitors for known aldosterone secretagogues from endothelial cells like nitric oxide, endothelin-1 or cylco-oxygenase products with their respective inhibitors L-NAME, BQ-123, BQ-788, the endothelin receptor 1A and 1B inhibitors respectively, and indomethacin did not alter the increase mediated by HCM.
These data show that the endothelial cells (a) stimulate aldosterone secretion from adrenocortical cells. (b) stimulation involves the phosphorylation of CREB. (c) the aldosterone secretion is independent of the classical cAMP dependent protein kinase A. (d) indicate the stimulating factor in HCM to be different from the known aldosterone stimulators endothelin-1, nitric oxide or cyclo-oxygenase products. Therefore, endothelial cells might play a hitherto unknown paracrine role in the regulation of steroid production and aldosterone release.