Janus Kinase 2 and Calcium Are Required for Angiotensin II-dependent Activation of Steroidogenic Acute Regulatory Protein Transcription in H295R Human Adrenocortical Cells

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.