Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension
Copyright policy )Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension
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.
- University of Adelaide Australia
- University Hospital of Lausanne Switzerland
- University of South Australia Australia
- Institute of Anatomy Switzerland
- University of Zurich Switzerland
Potassium Channels, Solute Carrier Family 12, mice, hypertension, Member 3, 10017 Institute of Anatomy, Knockout, 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, Ubiquitin-Protein Ligases, Dietary, knockout, 610 Medicine & health, Blood Pressure, 2700 General Medicine, Mice, Liddle Syndrome, Receptors, Animals, Humans, Solute Carrier Family 12, Member 3, Potassium Channels, Inwardly Rectifying, humans, Epithelial Sodium Channels, Mice, Knockout, disease models, Endosomal Sorting Complexes Required for Transport, Symporters, Animal, Sodium, Sodium, Dietary, Inwardly Rectifying, animals, Disease Models, Animal, kidney tubules, Kidney Tubules, Disease Models, Hypertension, Potassium, 570 Life sciences; biology, Drug
Potassium Channels, Solute Carrier Family 12, mice, hypertension, Member 3, 10017 Institute of Anatomy, Knockout, 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, Ubiquitin-Protein Ligases, Dietary, knockout, 610 Medicine & health, Blood Pressure, 2700 General Medicine, Mice, Liddle Syndrome, Receptors, Animals, Humans, Solute Carrier Family 12, Member 3, Potassium Channels, Inwardly Rectifying, humans, Epithelial Sodium Channels, Mice, Knockout, disease models, Endosomal Sorting Complexes Required for Transport, Symporters, Animal, Sodium, Sodium, Dietary, Inwardly Rectifying, animals, Disease Models, Animal, kidney tubules, Kidney Tubules, Disease Models, Hypertension, Potassium, 570 Life sciences; biology, Drug
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