Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension

Ronzaud, Caroline; Loffing-Cueni, Dominique; Hausel, Pierrette; Debonneville, Anne; Malsure, Sumedha Ram; Fowler-Jaeger, Nicole; Boase, Natasha A; Perrier, Romain; Maillard, Marc; Yang, Baoli; Stokes, John B; Koesters, Robert; Kumar, Sharad; Hummler, Edith; Loffing, Johannes; Staub, Olivier

doi:10.1172/JCI61110

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Ronzaud, C., Loffing-Cueni, D., Hausel, P., Debonneville, A., Malsure, S. R., Fowler-Jaeger, N., Boase, N. A., Perrier, R., Maillard, M., Yang, B., Stokes, J. B., Koesters, R., Kumar, S., Hummler, E., Loffing, J., & Staub, O. (2013). Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension. Journal of Clinical Investigation, 657–665. https://doi.org/10.1172/JCI61110

Abstract

The E3 ubiquitin ligase NEDD4-2 (encoded by the Nedd4L gene) regulates the amiloride-sensitive epithelial Na+ channel (ENaC/SCNN1) to mediate Na+ homeostasis. Mutations in the human β/γENaC subunits that block NEDD4-2 binding or constitutive ablation of exons 6-8 of Nedd4L in mice both result in salt-sensitive hypertension and elevated ENaC activity (Liddle syndrome). To determine the role of renal tubular NEDD4-2 in adult mice, we generated tetracycline-inducible, nephron-specific Nedd4L KO mice. Under standard and high-Na+ diets, co