Evolving research in nongenomic actions of aldosterone

Aldosterone is now recognized as an increasingly important contributor to cardiometabolic pathology via inflammatory and fibrosis-related pathways in addition to its classically described role in sodium and volume regulation. Consequently, much effort has been directed towards characterizing the molecular pathways involved in aldosterone-mediated fibrosis and inflammation. What was once viewed as straightforward steroid hormone biology is now appreciated as a highly complex and tightly regulated series of pathways and interactions. These recognitions have fuelled a multidisciplinary effort to identify precisely how aldosterone mediates intracellular activation of both genomic (latent) and nongenomic (rapid) mechanisms of influence. This review will explore recent novel pathways regulating aldosterone action, focusing on the nongenomic pathways.

Several recent discoveries have redefined our understanding of aldosterone interactions at the cellular level. This includes activation of the mineralocorticoid receptor at the plasma membrane instead of via classical nuclear hormone receptor interaction, and identification of novel cofactor scaffolding proteins that modify aldosterone influence at the cellular level. In addition, aldosterone activation of secondary messenger system cascades can occur directly and independent of mineralocorticoid receptor interaction.

Substantial progress in detailing the molecular biology of aldosterone regulation and action should facilitate study of how it exerts detrimental effects in cardiometabolic diseases. However, to date, the clinical impact of these discoveries has not been validated. Translational efforts are now required to determine if novel therapeutic targets can be developed.