Journal article
Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension
The Journal of clinical investigation, Vol.123(2), pp.657-665
02/01/2013
DOI: 10.1172/JCI61110
PMCID: PMC3561795
PMID: 23348737
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 beta/gamma ENaC 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, conditional KO mice displayed decreased plasma aldosterone but normal Na+/K+ balance. Under a high-Na+ diet, KO mice exhibited hypercalciuria and increased blood pressure, which were reversed by thiazide treatment Protein expression of beta ENaC, gamma ENaC, the renal outer medullary K+ channel (ROMK), and total and phosphorylated this vide-sensitive Na+Cl- cotransporter (NCC) levels were increased in KO kidneys. Unexpectedly, Scnn1a mRNA, which encodes the alpha ENaC subunit, was reduced and proteolytic cleavage of alpha ENaC decreased. Taken together, these results demonstrate that loss of NEDD4-2 in adult renal tubules causes a new form of mild, salt-sensitive hypertension without hyperkalemia that is characterized by upregulation of NCC, elevation of beta/gamma ENaC, but not alpha ENaC, and a normal Na+/K+ balance maintained by downregulation of ENaC activity and upregulation of ROMK.
Details
- Title: Subtitle
- Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension
- Creators
- Caroline Ronzaud - Univ Lausanne, Dept Pharmacol & Toxicol, CH-1005 Lausanne, SwitzerlandDominique Loffing-Cueni - University of ZurichPierrette Hausel - Univ Lausanne, Dept Pharmacol & Toxicol, CH-1005 Lausanne, SwitzerlandAnne Debonneville - Univ Lausanne, Dept Pharmacol & Toxicol, CH-1005 Lausanne, SwitzerlandSumedha Ram Malsure - Univ Lausanne, Dept Pharmacol & Toxicol, CH-1005 Lausanne, SwitzerlandNicole Fowler-Jaeger - Univ Lausanne, Dept Pharmacol & Toxicol, CH-1005 Lausanne, SwitzerlandNatasha A. Boase - Ctr Canc Biol, Dept Hematol, Adelaide, SA, AustraliaRomain Perrier - Univ Lausanne, Dept Pharmacol & Toxicol, CH-1005 Lausanne, SwitzerlandMarc Maillard - CHU Vaudois, Dept Nephrol, CH-1011 Lausanne, SwitzerlandBaoli Yang - University of Iowa, BioVentures CenterJohn B. Stokes - Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USARobert Koesters - Univ Paris 06, INSERM, UMRS 702, Tenon Hosp, Paris, FranceSharad Kumar - Ctr Canc Biol, Dept Hematol, Adelaide, SA, AustraliaEdith Hummler - Univ Lausanne, Dept Pharmacol & Toxicol, CH-1005 Lausanne, SwitzerlandJohannes Loffing - Univ Zurich, Inst Anat, CH-8057 Zurich, SwitzerlandOlivier Staub - Univ Lausanne, Dept Pharmacol & Toxicol, CH-1005 Lausanne, Switzerland
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.123(2), pp.657-665
- DOI
- 10.1172/JCI61110
- PMID
- 23348737
- PMCID
- PMC3561795
- NLM abbreviation
- J Clin Invest
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Publisher
- Amer Soc Clinical Investigation Inc
- Number of pages
- 9
- Grant note
- Swiss NCCR Kidney.ch Swiss Kidney Foundation 310030-141013; 310030-122243; 3100A0-102125/1 / Swiss National Science Foundation; Swiss National Science Foundation (SNSF); European Commission Leducq Foundation Transatlantic Network on Hypertension; Leducq Foundation APP1020755; 1002863 / National Health and Medical Research Council; National Health and Medical Research Council (NHMRC) of Australia
- Language
- English
- Date published
- 02/01/2013
- Academic Unit
- BioVentures Center; Obstetrics and Gynecology
- Record Identifier
- 9983557219402771
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