Angiotensin II-induced protein kinase D activation and regulation of aldosterone production

Abstract

Dysregulated aldosterone production leading to hypertension and its associated complications, such as congestive heart failure, cardiac fibrosis and renal failure, arc important public health concerns with a huge impact on the economy and patient quality of life. Thus, there is a high level of interest in the development of medical interventions and lifestyle changes to reduce the incidence of hypertension. Stimulation of the adrenal zona glomcrulosa with angiotensin II (Angll), potassium (K ) or adrenocorticotropic hormone (ACT! I), increases aldosterone production, to result in increased sodium and \ater retention. We ha\e recently shown a role for the serine/threonine protein kinase D (PKD) in the regulation of acute aldosterone synthesis upon Ang[( stimulation. In this study, using both molecular and pharmacological approaches, we demonstrate that Src family kinases and protein kinase C (PKC) activate PKD to increase aldosterone production in bovine adrenal glomerulosa cells. We have also shown that PKD positively regu lates expression of steroidogenic acute regulatory (StAR) protein, a protein required for cholesterol transport into the mitochondria, and aldosterone synthesis. PKD plays this role, in part, through activating members of the activating transcription factor (A TF)/cAMP response clement (CRE-) binding protein (CREB) family of leucine tipper transcription factors. Therefore, we hypothesite that PKC and Src family kinase-mediated PKD activation in response to Angll increases the phosphorylation and activation of ATF-2 and CREB, '' hich bind the StAR proximal promoter thereby resulting in induction of StAR expression and stimulation of steroidogenesis.