Ubiquitylation and the pathogenesis of hypertension
David H. Ellison
David H. Ellison
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Commentary

Ubiquitylation and the pathogenesis of hypertension

Abstract

Liddle syndrome is monogenic hypertension caused by mutations in the epithelial Na+ channel (ENaC) that interfere with its ubiquitylation by Nedd4-2. In this issue, Ronzaud and colleagues found that deleting Nedd4-2 from kidney tubules in adult mice led to ENaC accumulation, but not at the plasma membrane, as predicted from current models. Instead, abundance of the sodium chloride transporter NCC increased at the plasma membrane, and the mice have some features of increased NCC activity. Together, the results suggest that defective ubiquitylation of ENaC by Nedd4-2 may not fully explain Liddle syndrome and that Nedd4-2 modulates NCC more strongly.

Authors

David H. Ellison

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Figure 1

Models of ENaC and NCC regulation by Nedd4-2.

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Models of ENaC and NCC regulation by Nedd4-2. (A) Aldosterone (Aldo) int...
(A) Aldosterone (Aldo) interaction with the mineralocorticoid receptor (MR) induces SGK1 activity, which suppresses the ubiquitin ligase activity of Nedd4-2. Nedd4-2 normally catalyzes the addition of ubiquitin moieties (Ub) to ENaC (step i). Ubiquitylated ENaC is then removed from the plasma membrane (step ii) and undergoes degradation (or recycling) inside the cell (step iii). Poorly defined alternate pathways for SGK1 to stimulate ENaC independently of Nedd4-2 also exist. Ronzaud and colleagues (8) found that Nedd4-2 deletion increased in intracellular ENaC, suggesting that Nedd4-2 may affect step iii (dotted blue arrow) more than step ii. (B) Similar signaling pathway to NCC. An alternative pathway for SGK1 activation of NCC may involve WNK4, as described in text. In contrast with effects on ENaC, NCC abundance was increased at the plasma membrane by Nedd4-2 deletion, suggesting a defect at step ii, as shown by the dotted blue arrow. Note that sites of ubiquitylation on NCC have not been defined.