{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T20:54:16Z","timestamp":1793134456761,"version":"4.5.0"},"reference-count":36,"publisher":"National Academy of Sciences","issue":"20","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2012,5,15]]},"abstract":"<jats:p>\n                    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\n                    <jats:sup>+<\/jats:sup>\n                    Cl\n                    <jats:sup>\u2212<\/jats:sup>\n                    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\n                    <jats:sup>+<\/jats:sup>\n                    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\n                    <jats:italic>Xenopus laevis<\/jats:italic>\n                    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\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    ). WNK4 mRNA and protein expression were absent in WNK4\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    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\n                    <jats:sup>+\/+<\/jats:sup>\n                    but not WNK4\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    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\u2013dependent signaling pathway. Additionally, stimulation of aldosterone secretion by AngII, but not by a high-K\n                    <jats:sup>+<\/jats:sup>\n                    diet, was impaired in WNK4\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1200947109","type":"journal-article","created":{"date-parts":[[2012,5,1]],"date-time":"2012-05-01T22:57:49Z","timestamp":1335913069000},"page":"7929-7934","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":256,"title":["Activation of the renal Na\n                    <sup>+<\/sup>\n                    :Cl\n                    <sup>\u2212<\/sup>\n                    cotransporter by angiotensin II is a WNK4-dependent process"],"prefix":"10.1073","volume":"109","author":[{"given":"Mar\u00eda","family":"Casta\u00f1eda-Bueno","sequence":"first","affiliation":[{"name":"Molecular Physiology Unit, Instituto de Investigaciones Biom\u00e9dicas, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Tlalpan 14000 Mexico City, Mexico;"},{"name":"Departments of bNephrology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luz Graciela","family":"Cervantes-P\u00e9rez","sequence":"additional","affiliation":[{"name":"Departments of bNephrology and"},{"name":"Departments of cPharmacology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norma","family":"V\u00e1zquez","sequence":"additional","affiliation":[{"name":"Molecular Physiology Unit, Instituto de Investigaciones Biom\u00e9dicas, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Tlalpan 14000 Mexico City, Mexico;"},{"name":"Departments of bNephrology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norma","family":"Uribe","sequence":"additional","affiliation":[{"name":"Pathology, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Tlalpan 14000 Mexico City, Mexico;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheila","family":"Kantesaria","sequence":"additional","affiliation":[{"name":"Worldwide Research and Development, Pfizer, Inc., Groton, CT 06340;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciana","family":"Morla","sequence":"additional","affiliation":[{"name":"Centre de Recherche des Cordeliers, University Paris 6, Paris 75270, France;"},{"name":"Laboratoire de g\u00e9nomique, Physiologie et Physiopathologie R\u00e9nales, Centre National de la Recherche Scientifique, Paris 75270, France; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norma A.","family":"Bobadilla","sequence":"additional","affiliation":[{"name":"Molecular Physiology Unit, Instituto de Investigaciones Biom\u00e9dicas, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Tlalpan 14000 Mexico City, Mexico;"},{"name":"Departments of bNephrology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alain","family":"Doucet","sequence":"additional","affiliation":[{"name":"Centre de Recherche des Cordeliers, University Paris 6, Paris 75270, France;"},{"name":"Laboratoire de g\u00e9nomique, Physiologie et Physiopathologie R\u00e9nales, Centre National de la Recherche Scientifique, Paris 75270, France; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dario R.","family":"Alessi","sequence":"additional","affiliation":[{"name":"Medical Research Council (MRC) Protein Phosphorylation Unit, University of Dundee, Dundee, DD1 5EH, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerardo","family":"Gamba","sequence":"additional","affiliation":[{"name":"Molecular Physiology Unit, Instituto de Investigaciones Biom\u00e9dicas, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Tlalpan 14000 Mexico City, Mexico;"},{"name":"Departments of bNephrology and"},{"name":"Nephrology, 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