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. (c) 2005 Elsevier Inc. All rights reserved.