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1 Division of Nephrology & Hypertension and Department of Clinical Research, University of Bern, Bern, Switzerland
2 Department of Pharmacology & Toxicology, University of Lausanne, Lausanne, Switzerland
3 INSERM U409, Faculty of Medicine, University of Xavier Bichat, Paris, France
* To whom correspondence should be addressed. E-mail: Olivier.Staub{at}ipharm.unil.ch.
The epithelial Na+ channel (ENaC) is regulated by the ubiquitin-protein ligase Nedd4-2 via interaction with ENaC PY-motifs. These PY-motifs are mutated/deleted in Liddle's syndrome, resulting in elevated Na+ reabsorption and hypertension explained partly by impaired ENaC/Nedd4-2 interaction. We hypothesized that Nedd4-2 is a susceptibility gene for hypertension and screened 856 renal patients and healthy controls for mutations in a subset of exons of the human Nedd4-2 gene that are relevant for ENaC regulation by PCR/SSCP. Several variants were identified, and one non-synonymous mutation (Nedd4-2- P355L) was further characterized. This mutation next to the 3' donor site of exon 15, does not affect in vitro splicing of Nedd4-2 mRNA. However, in the Xenopus oocyte expression system, Nedd4-2-P355L dependant ENaC inhibition was weaker as compared to Nedd4-2- WT and this difference depended on the presence of intact PY-motifs on ENaC. This could not be explained by the amount of wild-type or mutant Nedd4-2 co-immunoprecipitating with ENaC. When the phosphorylation level of human Nedd4-2 Ser448 (known to be phosphorylated by the Sgk1 kinase) was determined with a specific anti-pSer448 antibody, we observed stronger basal phosphorylation of Nedd4-2-P355L. Both the phosphorylation level and the accompanying amiloride-sensitive Na+ currents could be further enhanced to approximately the same levels by co-expressing Sgk1. In addition, the role of the two other putative Sgk1 phosphorylation sites (S342 and T367) appears also to be affected by the P355L mutation. The differential phosphorylation status between wild-type and mutant Nedd4-2 provides an explanation for the different potential to inhibit ENaC activity.
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