Abstract
Angiotensin II- and K+-stimulated aldosterone production in the adrenocortical glomerulosa cells requires induction of the steroidogenic acute regulatory protein (StAR). While both agents activate Ca2+ signaling, the mechanisms leading to aldosterone synthesis are distinct, and the angiotensin II response cannot be mimicked by K+. We previously reported that StAR mRNA levels and promoter-reporter gene activity in transiently transfected H295R human adrenocortical cells were stimulated by angiotensin II but not by K+ treatment. The current study focused on identifying signaling pathways activated by angiotensin II that contribute to StAR transcriptional activation. We show that the angiotensin II-stimulated transcriptional activation of StAR was dependent upon influx of external calcium and requires protein kinase C activation. Furthermore we describe for the first time that the Janus tyrosine kinase family member, JAK2, was activated by angiotensin II treatment of H295R cells. Treatment of the cells with AG490, a selective inhibitor of JAK2, blocked JAK2 activation and StAR reporter gene activity and inhibited steroid production. Taken together these studies describe a novel pathway controlling StAR expression and steroidogenesis in adrenocortical cells.
Highlights
The two major physiological regulators of aldosterone synthesis in the adrenal zona glomerulosa are angiotensin II (Ang II)1 and extracellular Kϩ [1]
To determine whether calcium signaling is sufficient for the Ang II-dependent steroidogenic acute regulatory protein (StAR) transcriptional response, thapsigargin (Tg) treatment was used to mimic the Ang II-stimulated calcium signaling in H295R cells
The importance of extracellular Ca2ϩ in mediating aldosterone production is well established, and we report a direct link between Ang II-stimulated influx of extracellular Ca2ϩ and StAR gene expression
Summary
The two major physiological regulators of aldosterone synthesis in the adrenal zona glomerulosa are angiotensin II (Ang II) and extracellular Kϩ [1]. Inhibition of ERK1/2 activation did not inhibit the Ang II-stimulated increase in aldosterone synthesis, suggesting this pathway is not involved in the Ang II-dependent steroidogenic response in this cell line [33]. The evidence that tyrosine kinase signaling pathway(s) may be part of the Ang II response in adrenocortical cells was suggested by studies that reported genistein to be an inhibitor of aldosterone production, calcium influx via CRAC channels in bovine glomerulosa cells, and 3--hydroxysteroid dehydrogenase activity in H295R cells (29 –31). The approach was twofold: first, to test the contribution of release of intracellular calcium stores versus influx of extracellular calcium on Ang II-dependent transcriptional activation of StAR, and second, to determine whether Ang II activates JAK and/or ERK1/2 signaling and increases StAR transcription in H295R cells
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