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Submitted on July 30, 2003
Accepted on October 22, 2003
1 Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama City, 700-8558, Japan
* To whom correspondence should be addressed. E-mail: fumiotsu{at}md.okayama-u.ac.jp.
We have uncovered a functional bone morphogenetic protein (BMP) and activin system complete with ligands (BMP-6 and activin 
A/B), receptors (ALK-2, -3, -4, ActR-II and BMPR-II) and the binding protein, follistatin, in the human adrenocortical cell line, H295R. Administration of activin and BMP-6 to cultures of H295R cells caused concentration-responsive increases in aldosterone production. The mRNA levels of steroidogenic acute regulatory protein (StAR) or P450 steroid side-chain cleavage enzyme, the rate-limiting steps of adrenocortical steroidogenesis, were enhanced by activin and BMP-6. Activin and BMP-6 also activated the transcription of StAR as well as the late-step steriodogenic enzyme, CYP11B2. Activin enhanced ACTH-, forskolin- or dibutyryl-cAMP-, but not angiotensin II (Ang II)-induced aldosterone production, whereas BMP-6 specifically augmented Ang II-induced aldosterone production. Activin and ACTH but not BMP-6 increased cAMP production. Follistatin, which inhibits activin actions by binding, suppressed basal and ACTH-induced aldosterone secretion but failed to affect Ang II-induced aldosterone level. Furthermore, MAPK signaling appeared to be involved in aldosterone production induced by Ang II and BMP-6 since an inhibitor of MAPK activation, U0126, reduced the level of aldosterone synthesis stimulated by Ang II and BMP-6 but not activin. In addition, Ang II reduced the expression levels of BMP-6 but increased that of activin B, while ACTH had no effect on these levels. Collectively, the present data suggest that activin acts to regulate adrenal aldosterone synthesis predominantly by modulating the ACTH-cAMP-PKA signaling cascade whereas BMP-6 works primarily by modulating the Ang II-MAPK cascade in human adrenal cortex in an autocrine/paracrine fashion. (250 words)
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