Functional zonation of the adrenal cortex is a consequence of the zone-specific expression of P450c17 (CYP17A1) and its cofactors.
Activin and
inhibin peptides are differentially produced within the zones of the adrenal cortex and have been implicated in steroidogenic control. In this study, we investigated whether
activin and
inhibin can function as intermediates in functional zonation of the human adrenal cortex.
Activin A suppressed CYP17A1 expression and P450c17 function in adrenocortical cell lines as well as in primary adrenal cell cultures.
Inhibin βA-subunit
mRNA and
activin A protein levels were found to be increased up to 1,900-fold and 49-fold, respectively, after
protein kinase C (PKC) stimulation through PMA or
angiotensin II in H295R
adrenocortical carcinoma cells. This was confirmed in HAC15 cells and for PMA in primary adrenal cell cultures. Both PMA and Ang II decreased CYP17A1 expression in the adrenocortical cell lines, whereas PMA concurrently suppressed CYP17A1 levels in the primary cultures. Inhibition of
activin signaling during PKC stimulation through silencing of the
inhibin βA-subunit or blocking of the
activin type I receptor opposed the PMA-induced downregulation of CYP17A1 expression and P450c17 function. In contrast, PKA stimulation through adrenocorticotrophin or
forskolin increased expression of the
inhibin α-subunit and
betaglycan, both of which are antagonists of
activin action. These data indicate that
activin A acts as a PKC-induced paracrine factor involved in the suppression of CYP17A1 in the zona glomerulosa and can thereby contribute to functional adrenocortical zonation.