Liddle syndrome is a form of early onset, severe hypertension that is caused by mutations in the NEDD4 gene. NEDD4 is a ubiquitin ligase, which mediates the destruction of target proteins.
Liddle's syndrome is hypothesized to be caused by the inability of mutant NEDD4 to induce destruction of the kidney sodium channel ENaC, perturbing sodium homeostasis to induce hypertension. In the Journal of Clinical Investigation, Olivier Staub and colleagues at the University of Lausanne investigated the effects of mutant NEDD4 in the kidney.
Staub and colleagues engineered a mouse that only expressed mutant NEDD4 in the renal tubules. Mutant mice exhibited increased ENaC but did not have higher blood sodium levels. These results demonstrate that the current model of Liddle's syndrome is incorrect. Interestingly, expression of mutant NEDD4 led to an increase in NCC, a sodium/chloride transporter, which could contribute to the elevated sodium and hypertension associated with Liddle's syndrome.
These results indicate that NEDD4 could be a therapeutic target for the treatment of hypertension. In a companion commentary, David Ellison of Oregon Health and Science University discusses how these findings will affect our understanding of hypertension.
TITLE:Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension
ACCOMPANYING COMMENTARY: Ubiquitylation and the pathogenesis of hypertension