Janus kinase 2 signaling in the angiotensin II-dependent activation of StAR expression

Angiotensin II (Ang ll)-stimulated aldosterone production in adrenocortical glomerulosa cells requires de novo expression of the steroidogenic acute regulatory protein (StAR). We previously reported that StAR mRNA levels and promoter-reporter gene activity in transiently transfected H295R human adrenocortical cells were stimulated by Ang II and the goals for the current study were to identify signaling pathways activated by Ang II that contribute to StAR transcriptional activation. Using StAR promoter-reporter gene activity and pharmacological inhibition of signaling pathways, we have shown that Ang II-stimulated StAR transcription in H295R cells is dependent upon both influx of external Ca2+ and tyrosine kinase signaling and is enhanced by protein kinase C and mitogen-activated protein kinase (ERK1/2) activation. In particular, Janus tyrosine kinase-2 (Jak2) activation was increased with Ang-II treatment of H295R cells and the select Jak2 inhibitor, AG490, blocked Ang II-dependent Jak2 activation, StAR reporter gene activity, and steroid production. The Ang II-dependent, but not (BU)(2)cAMP-dependent, induction of StAR mRNA was also blocked by AG490 and shown to be sensitive to cycloheximide treatment. Together our data support Jak2 as a novel pathway in the Ang II-dependent activation of StAR expression and steroidogenesis in adrenocortical cells and indicate a requirement for ongoing protein synthesis in Ang II-mediated StAR transcription.