期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 109, 期 20, 页码 7929-7934出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1200947109
关键词
distal tubule; diuretics; thiazide; renin-angiotensin-aldosterone system
资金
- Wellcome Trust [091415]
- Fondation Leducq
- Mexican Council of Science and Technology [165815]
- Consejo Nacional de Ciencia y Tecnologia Mexico
- Universidad Nacional Autonoma de Mexico
- Medical Research Council [MC_U127070193] Funding Source: researchfish
- MRC [MC_U127070193] Funding Source: UKRI
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 pseudoal-dosteronism 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据