Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension
Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension
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DOI：
10.1172/jci61110
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发表时间：
2013-02-01
影响因子：
15.9
通讯作者：
Staub, Olivier
中科院分区：
文献类型：
--
作者：
Ronzaud, Caroline;Loffing-Cueni, Dominique;Staub, Olivier
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.
