Aldosterone Producing Adrenal Adenomas are Characterized by Activation of Calcium/Calmodulin-dependent Protein Kinase (CaMK) Dependent Pathways

Abstract

Primary aldosteronism is the most prevalent cause of secondary hypertension. However, insights in pathophysiological mechanisms resulting in autonomous aldosterone secretion are limited. Although transcriptional regulators of aldosterone synthase (CYP11B2) including calcium-binding calmodulin kinase (CaMK) dependent pathways have been defined in vitro, it remains uncertain whether these mechanisms play a role in the context of dysregulated steroidogenesis in aldosterone producing adrenadenomas. Thus, we compared expression and activation of key components of CaMK pathways in aldosterone producing adenomas (APAs) with normal adrenals glands (NAGs). As expected, aldosterone synthase expression in APAs was significantly higher in comparison to NAGs, suggesting transcriptional activation as a contributing factor of aldosterone excess. Along the same line, CaMKI was significantly upregulated in APAs on the mRNA and protein level. Furthermore, immunohistochemistry revealed nuclear localization of CaMKI in these tumors. The phosphorylation of CREB, a target protein for CaMKI was increased, which could represent a further stimulation of aldosterone synthase transcription. In summary, this study provides indirect evidence for a causative involvement of the CaM kinase signaling pathway in human aldosterone producing adenomas.

Key words

CaMKI - autonomous aldosterone secretion - CaM kinase dependent pathways - primary aldosteronism

References

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