The Serum and Glucocorticoid regulated Kinase (SGK1) is a component of the pathway mediating activation of the epithelial sodium channel, ENaC, in the aldosterone-sensitive distal nephron (ASDN). Aldosterone is released when the body needs more sodium or when blood pressure is low, leading to increased SGK1 transcription and translation (7, 23). SGK1 phosphorylates the E3 ubiquitin ligase Nedd4-2 (9, 25), which normally adds ubiquitin onto ENaC at the cell surface triggering its endocytosis (17). In vitro, phosphorylation of Nedd4-2 by SGK1 leads to a decrease in the interaction between Nedd4-2 and ENaC. This results in increased ENaC at the cell surface, and an increase in sodium transport (9, 25). But SGK1 can regulate ENaC proteins lacking Nedd4-2-binding (PY) motifs (1, 8). Insulin also activates ENaC through SGK1 (19, 27), and SGK1 contributes to upregulation of αENaC transcription in the ASDN (29). SGK1 also regulates other ion channels and transporters (reviewed in (18, 20)).

Phenotype of SGK1-/-mouse. In 2002 Wulff et al. described the phenotype of a SGK1 knockout (SGK1-/-) mouse (28). Fejes-Tóth et al. now report a second SGK1 knockout mouse model (11). Similar to the previously described SGK1-/-mice the new mouse line showed no gross abnormalities under a normal salt diet. This is in sharp contrast to the severe phenotypes seen in mineralocorticoid receptor (3) and ENaC (2, 16, 22) knockout mouse lines. However, both SGK1 knockout mouse lines did show abnormalities when they were challenged with a low salt diet. Both groups report that on a low salt diet SGK1+/+ and SGK1-/-mice decreased their urinary salt loss, but whereas SGK1+/+ mice reduced their sodium excretion to near zero, significant urinary salt wasting occurred in the SGK1-/-mice. Salt wasting suggests that lack of SGK1 prevented upregulation of ENaC, so Na+ was lost in the urine. Measurements were made to ask if ENaC activity was altered. Wulff et al. reported a lowered amiloride-sensitive transepithelial potential measured in isolated collecting ducts (CD) of SGK1-/-mice compared to SGK1+/+ mice (28). In contrast, Fejes-Tóth et al. report an increased amiloride-sensitive sodium current measured by whole cell patch clamp in isolated collecting ducts of SGK1-/-mice, compared to SGK1+/+ mice (11). The reason for this discrepancy is not clear. However, under salt depleted conditions both mouse lines show hyperaldosteronism, and this may account for the upregulation of ENaC in the new SGK1-/-mice, similar to the observation reported for the colon of the first SGK1-/-mouse (24). Both groups measured ENaC activity after the mice had been on a low salt diet for 2-3 days. Most previous animal studies have focussed on a shorter term effect of aldosterone on SGK1 (4), however these SGK1 knockout papers do not address this timeframe. The SGK1-/-mice models do suggest that SGK1 is required to prevent renal salt wasting, however the data of Fejes-Tóth et al. suggest there are ENaC-independent pathways that SGK1 controls to achieve this ((11), see below). Chronic aldosterone treatment or salt depletion in mice does lead to sustained upregulation of SGK1 transcription, in distal kidney, over a period of at least 6 days (13). New data from Fejes-Tóth et al. show that ENaC activity is upregulated normally with chronic aldosterone treatment of the SGK1-/-mice (11). SGK1 and ENaC processing. The α and γENaC proteins undergo proteolytic cleavage during and/or after trafficking to the cell surface (5, 6, 15). Increased activity