The
ubiquitin ligase NEDD4L participates in plasma volume and blood pressure regulation by controlling expression of the
epithelial sodium channel (ENaC). Genetic impairment of EnaC-Nedd4L-Proteasome system caused a rare mendelian hereditary human
hypertension,
Liddle syndrome. This finding suggested that Nedd4L is playing an important role in pathogenesis for hypertensive disorders. This prompted us to test a possible involvement of NEDD4L for the development of
sodium-sensitive
hypertension in Dahl
salt-sensitive (DS) rats and its normotensive littermate Dahl
salt-resistant (DR) rats. First, we analyzed the transcriptional diversity of rat Nedd4L gene and observed several
isoforms with and without
calcium-dependent membrane binding (C2) domain at the N-terminal of the
protein as we found in human and mouse before. Then, we analyzed the expression of rat NEDD4L in the kidney of both DS and DR under high and low
sodium regimens. NEDD4L expression examined by quantitative PCR technique revealed lower expression of NEDD4L transcripts in DS rats under either diet compared to DR animals; additionally, NEDD4L expression was significantly increased with
sodium loading. Using in situ hybridization experiments, rat NEDD4L was predominantly expressed in distal nephron in a manner dependent on both
sodium regimen and genetic background. A similar histological distribution pattern was observed in human kidney. The expression of NEDD4L in distal nephron and its response to chronic
sodium loading suggest that it participates in the functioning of this segment in
sodium reabsorption. This response was impaired in genetically
sodium-sensitive animals. These findings suggested that Nedd4L gene products were involved in the development of
salt-sensitive
hypertension.