Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension
| Autor: | Caroline Ronzaud, Natasha A. Boase, Johannes Loffing, Baoli Yang, Romain Perrier, Nicole Fowler-Jaeger, Edith Hummler, Dominique Loffing-Cueni, Sumedha Malsure, Marc Maillard, Sharad Kumar, Pierrette Hausel, Olivier Staub, Robert Koesters, Anne Debonneville, John B. Stokes |
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| Přispěvatelé: | Ronzaud, Caroline, Loffing-Cueni, Dominique, Hausel, Pierrette, Debonneville, Anne, Malsure, Sumedha Ram, Fowler-Jaeger, Nicole, Boase, Natasha Anne, Perrier, Romain, Maillard, Marc, Yang, Baoli, Stokes, John B, Koesters, Robert, Kumar, Sharad, Hummler, Edith, Loffing, Johannes, Staub, Olivier, University of Zurich |
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Epithelial sodium channel
10017 Institute of Anatomy Animals Blood Pressure Disease Models Animal Endosomal Sorting Complexes Required for Transport/deficiency Endosomal Sorting Complexes Required for Transport/genetics Epithelial Sodium Channels/metabolism Humans Hypertension/etiology Hypertension/genetics Kidney Tubules/physiopathology Liddle Syndrome/etiology Liddle Syndrome/genetics Mice Mice Knockout Potassium/blood Potassium/urine Potassium Channels Inwardly Rectifying/metabolism Receptors Drug/metabolism Sodium/blood Sodium/urine Sodium Dietary/administration & dosage Sodium Dietary/adverse effects Symporters/metabolism Ubiquitin-Protein Ligases/deficiency Ubiquitin-Protein Ligases/genetics Nedd4 Ubiquitin Protein Ligases Receptors Drug knockout 2700 General Medicine 030204 cardiovascular system & hematology chemistry.chemical_compound 0302 clinical medicine Solute Carrier Family 12 Member 3 humans 0303 health sciences Aldosterone Symporters Chemistry General Medicine animals Kidney Tubules kidney tubules Hypertension Research Article medicine.medical_specialty mice hypertension Ubiquitin-Protein Ligases 610 Medicine & health macromolecular substances 03 medical and health sciences Liddle Syndrome Internal medicine medicine Potassium Channels Inwardly Rectifying Epithelial Sodium Channels 030304 developmental biology NEDD4L disease models Endosomal Sorting Complexes Required for Transport urogenital system Sodium Sodium Dietary Endocrinology Symporter Potassium Commentary ROMK 570 Life sciences biology Cotransporter Homeostasis |
| Zdroj: | JOURNAL OF CLINICAL INVESTIGATION The Journal of clinical investigation Journal of Clinical Investigation, vol. 123, no. 2, pp. 657-665 |
| Popis: | 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, 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 βENaC, γENaC, the renal outer medullary K+ channel (ROMK), and total and phosphorylated thiazide-sensitive Na+Cl- cotransporter (NCC) levels were increased in KO kidneys. Unexpectedly, Scnn1a mRNA, which encodes the αENaC subunit, was reduced and proteolytic cleavage of αENaC 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 β/γENaC, but not αENaC, and a normal Na+/K+ balance maintained by downregulation of ENaC activity and upregulation of ROMK. Refereed/Peer-reviewed |
| Databáze: | OpenAIRE |
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