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.
Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.
Caroline
C
Ronzaud
Dominique
D
Loffing-Cueni
Pierrette
P
Hausel
Anne
A
Debonneville
Sumedha Ram
SR
Malsure
Nicole
N
Fowler-Jaeger
Natasha A
NA
Boase
Romain
R
Perrier
Marc
M
Maillard
Baoli
B
Yang
John B
JB
Stokes
Robert
R
Koesters
Sharad
S
Kumar
Edith
E
Hummler
Johannes
J
Loffing
Olivier
O
Staub
D000818:Animals; D001794:Blood Pressure; D004195:Disease Models, Animal; D056827:Endosomal Sorting Complexes Required for Transport / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D053503:Epithelial Sodium Channels / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D007684:Kidney Tubules / Q000503:physiopathology*; D056929:Liddle Syndrome / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D000075702:Nedd4 Ubiquitin Protein Ligases; D011188:Potassium / Q000097:blood / Q000652:urine; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D011955:Receptors, Drug / Q000378:metabolism*; D012964:Sodium / Q000097:blood / Q000652:urine; D012982:Sodium, Dietary / Q000008:administration & dosage / Q000009:adverse effects; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels; C510693:Kcnj1 protein, mouse; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; C578875:Slc12a3 protein, mouse; D012982:Sodium, Dietary; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters; D012964:Sodium; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; C000618485:Nedd4L protein, human; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases; D011188:Potassium