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Submitted on June 14, 2006
Accepted on September 5, 2006
Division of Endocrinology, G.V. (Sonny) Montgomery VA Medical Center, and Department of Medicine and Pharmacology and Toxicology, The University of Mississippi Medical Center, Jackson, MS 39216, USA
* To whom correspondence should be addressed. E-mail: dromero{at}medicine.umsmed.edu.
Protein kinases are important mediators in intracellular signaling. Angiotensin II is the most important modulator of adrenal zona glomerulosa cell physiology. Angiotensin II regulates steroidogenesis and proliferation among many other metabolic processes. H295R human adrenal cells are a widely used experimental model to study adrenal cell physiology and metabolism. We screened for protein kinase expression levels using the Kinetwork system in H295R cells after 3 h Angiotensin II treatment. Protein kinase D (PKD) was the protein kinase that suffers the most dramatic changes. PKD is a member of a new class of serine/threonine protein kinases that is activated by phosphorylation. Our studies indicated that Angiotensin II time- and dose-dependently increased PKD phosphorylation, which occurred within 2 min of Angiotensin II treatment and at concentrations as low as 1 nM. PKD phosphorylation was also dose-dependently increased by the protein kinase C (PKC) activator PMA. Angiotensin II-mediated PKD phosphorylation was blocked by several PKC inhibitors. Furthermore, PKC
translocation inhibitor peptide decreased Angiotensin II-mediated PKD phosphorylation and PKC downregulation by RNA interference also decreased PKD phosphorylation mediated by Angiotensin II. Cotransfection of constitutively active PKD mutant constructs upregulated aldosterone synthase and 11
-hydroxylase expression in reporter assays. Constitutively active PKD mutants increased aldosterone and cortisol secretion under Ang II stimulatory conditions. This study reveals that PKD is an intracellular signaling mediator of Angiotensin II regulation of steroidogenesis in human adrenal cells. These data provide new insights into the molecular mechanisms involved in Angiotensin II-induced physiological and pathophysiological events in adrenal cells.
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