Purpose of review: The aldosterone/mineralocorticoid receptor system plays an important role in the long-term blood pressure control through Na homeostasis. Its overactivation has been implicated in salt-sensitive hypertension. Excessive salt intake augments the function of mineralocorticoid receptor, despite lowering circulating aldosterone levels, but the mechanism had long been elusive. Recently, Rac1, a member of Rho family small GTP-binding proteins, has emerged as a novel ligand-independent modulator of mineralocorticoid receptor activity. In this review, the roles of Rac1 in the pathogenesis of salt-sensitive hypertension and kidney injury have been summarized.
Recent findings: Genetic engineering studies have highlighted the new aspects of Rac1 and its regulators in salt-sensitive hypertension and cardiac and renal disease. New evidence shows the essential roles of Rac1 in salt-evoked paradoxical mineralocorticoid receptor activation observed in salt-sensitive models and in renal tubular Na reabsorption through reduced nicotinamide-adenine dinucleotide phosphate oxidase-mediated oxidative stress or direct regulation of Na transporters.
Summary: The emerging concept of 'ligand-independent aberrant mineralocorticoid receptor activation by Rac1' in the pathogenesis of salt-sensitive hypertension and kidney injury has been reviewed. Rac inhibition, in addition to mineralocorticoid receptor blockade and salt restriction, would be a new promising strategy for the treatment of salt-sensitive hypertension.