**4. Liddle Syndrome and ENaC**

Liddle syndrome is a type of hereditary hypertension described by Liddle et al., in 1963, that has an autosomal-dominant inheritance pattern similar to that of primary aldosteronism, without elevated renin and aldosterone. Patients with Liddle syndrome exhibit hypokalemic alkalosis. The mechanism of this disease was discovered by Lifton et al. in 1995. [38,39] They found a gene mutation common to the P2 region of the proline-rich PY motif at the COOH terminus of β and γ ENaC. In 1996, Staub et al. [40] identified NEDD4 (neural precursor cell-expressed, developmentally, down-regulated 4) as a ubiquitinating enzyme (E3) protein that binds to this PY motif. Subsequent studies showed that NEDD4 ubiquitinates the Lys residue at the NH2 terminus by binding to the PY motif of ENaC, and the ubiquitinated ENaC was internalized into the cells where it was transported to the proteasome and was then degraded [41–43]. The post-translational modification and degradation of this protein is critical for the expression of ENaC on the cell membrane surface, and its physiological half-life is a maximum of one hour. A mutation of the PY motif results in impairments of ENaC ubiquitination via Nedd4 inhibition, sustained ENaC expression on the cell surface membrane, and enhanced sodium reabsorption; thus, a model of salt-sensitive hypertension was proposed. Snyder et al. concurrently revealed a similar mechanism [44].

Sodium reabsorption mediated by ENaC in ASDN does not possess su fficient physiological compensatory/feedback mechanisms such as TGF in the upstream nephron and the myogenic reaction in a fferent arterioles. Therefore, the sodium reabsorption mechanism fails due to a dysfunctional ENaC-Nedd4 system, whether it is a gain or loss of function, and can eventually lead to abnormal blood pressure, without e ffective intra-renal correction.
