NDLI: Activation of the renal Na+:Cl− cotransporter by angiotensin II is a WNK4-dependent process

Content Provider	PubMed Central
Author	María, Castañeda-bueno Cervantes-pérez, Luz Graciela Vázquez, Norma Uribe, Norma Kantesaria, Sheila Morla, Luciana Bobadilla, Norma A. Doucet, Alain Alessi, Dario R. Gamba, Gerardo
Abstract	Pseudohypoaldosteronism type II is a salt-sensitive form of hypertension with hyperkalemia in humans caused by mutations in the with-no-lysine kinase 4 (WNK4). Several studies have shown that WNK4 modulates the activity of the renal Na+Cl− cotransporter, NCC. Because the renal consequences of WNK4 carrying pseudoaldosteronism type II mutations resemble the response to intravascular volume depletion (promotion of salt reabsorption without K+ secretion), a condition that is associated with high angiotensin II (AngII) levels, it has been proposed that AngII signaling might affect WNK4 modulation of the NCC. In Xenopus laevis oocytes, WNK4 is required for modulation of NCC activity by AngII. To demonstrate that WNK4 is required in the AngII-mediated regulation of NCC in vivo, we used a total WNK4-knockout mouse strain (WNK4−/−). WNK4 mRNA and protein expression were absent in WNK4−/− mice, which exhibited a mild Gitelman-like syndrome, with normal blood pressure, increased plasma renin activity, and reduced NCC expression and phosphorylation at T-58. Immunohistochemistry revealed normal morphology of the distal convoluted tubule with reduced NCC expression. Low-salt diet or infusion of AngII for 4 d induced phosphorylation of STE20/SPS1-related proline/alanine-rich kinase (SPAK) and of NCC at S-383 and T-58, respectively, in WNK4+/+ but not WNK4−/− mice. Thus, the absence of WNK4 in vivo precludes NCC and SPAK phosphorylation promoted by a low-salt diet or AngII infusion, suggesting that AngII action on the NCC occurs via a WNK4-SPAK–dependent signaling pathway. Additionally, stimulation of aldosterone secretion by AngII, but not by a high-K+ diet, was impaired in WNK4−/− mice.
Related Links	http://dx.doi.org/10.1073/pnas.1200947109
Ending Page	7934
Page Count	6
Starting Page	7929
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	20
Volume Number	109
Language	English
Publisher	National Academy of Sciences
Publisher Date	2012-05-15
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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