The top panel, A, illustrates several mechanisms responsible for ENaC regulation in the kidney. ENaC open probability and activity is regulated by shear stress, proteolytic cleavage, palmitoylation (indicated by blue cytoplasmic arrowheads), and extracellular [Na+]. Nedd4–2 facilitates ENaC ubiquitination and endocytosis. Aldosterone activates MR, increasing transcription of αENaC and the regulatory kinase Sgk1. However, in the salt sensitive kidney, panel B, MR is activated by the GTPase Rac1, independent of aldosterone. Rac1 also increases ROS production via NOX, which activates ENaC. Increased proteolytic activation of ENaC has also been reported, however, further work is needed to establish which proteases may be responsible.