2.4.1. NEDD4-2-Mediated Ubiquitylation and ENaC

ENaC, consisting of three subunits, α, β, and γ, is a primary regulator of sodium reabsorption in the CNT and CD [49,50]. It has been reported that gain-of-function mutations of SCNN1B and SCNN1G cause Liddle's syndrome, which is characterized by salt-sensitive hypertension, hypokalemia, metabolic alkalosis, and low aldosterone levels [51–54]. This phenotype is induced by the disruption or elimination of PY motifs in the β- and γ-subunits of ENaC. Provided that NEDD4-2 ubiquitylates ENaC and regulates its membrane expression and activity [55–58], these mutations cause both increased channel expression and intrinsic activity with a consequent increase of sodium reabsorption. When the renin-angiotensin-aldosterone system (RAAS) is inactivated, NEDD4-2 continuously ubiquitylates

ENaC and downregulates ENaC abundance. When RAAS is activated, aldosterone-induced Sgk1 phosphorylates NEDD4-2, resulting in the recruitment of 14-3-3 adaptor proteins. These proteins inhibit the association between NEDD4-2 and ENaC, thereby leading to the elevation of ENaC levels [59,60]. Consistently, several studies have demonstrated that mice lacking functional NEDD4-2 exhibit high levels of ENaC and salt-sensitive hypertension [61,62]. In humans, several reports indicated that common variants in *NEDD4L* (encoding NEDD4-2) are associated with BP disorder [63–66].
