Liddle's syndrome is a human genetic disease affecting the epithelial sodium channel ENaC and characterized by increased renal sodium reabsorption and hypertension. To better understand the mechanisms implicated in the regulation of ENaC in the kidney, we have generated mice knockout for the ubiquitin-ligase Nedd4-2, a well-known regulator of the channel that is involved in its degradation. Surprisingly, the salt-sensitive hypertension observed in these mice was due to over-active NCC, another renal sodium transporter, and not to ENaC whose function was rather decreased. Our paper, recently published in the Journal of Clinical Investigation, opens new routes for the discovery of novel anti-hypertensive treatments.