{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:35:07Z","timestamp":1791275707724,"version":"4.1.0"},"reference-count":40,"publisher":"National Academy of Sciences","issue":"11","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2009,3,17]]},"abstract":"<jats:p>\n                    Mutations in the kinase WNK4 cause pseudohypoaldosteronism type II (PHAII), a syndrome featuring hypertension and high serum K\n                    <jats:sup>+<\/jats:sup>\n                    levels (hyperkalemia). WNK4 has distinct functional states that regulate the balance between renal salt reabsorption and K\n                    <jats:sup>+<\/jats:sup>\n                    secretion by modulating the activities of renal transporters and channels, including the Na-Cl cotransporter NCC and the K\n                    <jats:sup>+<\/jats:sup>\n                    channel ROMK. WNK4's functions could enable differential responses to intravascular volume depletion (hypovolemia) and hyperkalemia. Because hypovolemia is uniquely associated with high angiotensin II (AngII) levels, AngII signaling might modulate WNK4 activity. We show that AngII signaling in\n                    <jats:italic>Xenopus<\/jats:italic>\n                    oocytes increases NCC activity by abrogating WNK4's inhibition of NCC but does not alter WNK4's inhibition of ROMK. This effect requires AngII, its receptor AT1R, and WNK4, and is prevented by the AT1R inhibitor losartan. NCC activity is also increased by WNK4 harboring mutations found in PHAII, and this activity cannot be further augmented by AngII signaling, consistent with PHAII mutations providing constitutive activation of the signaling pathway between AT1R and NCC. AngII's effect on NCC is also dependent on the kinase SPAK because dominant-negative SPAK or elimination of the SPAK binding motif in NCC prevent activation of NCC by AngII signaling. These effects extend to mammalian cells. AngII increases phosphorylation of specific sites on SPAK and NCC that are necessary for activation of each in mpkDCT cells. These findings place WNK4 in the signaling pathway between AngII and NCC, and provide a mechanism by which hypovolemia maximizes renal salt reabsoprtion without concomitantly increasing K\n                    <jats:sup>+<\/jats:sup>\n                    secretion.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0813238106","type":"journal-article","created":{"date-parts":[[2009,2,24]],"date-time":"2009-02-24T22:56:26Z","timestamp":1235516186000},"page":"4384-4389","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":223,"title":["Angiotensin II signaling increases activity of the renal Na-Cl cotransporter through a WNK4-SPAK-dependent pathway"],"prefix":"10.1073","volume":"106","author":[{"given":"Pedro","family":"San-Cristobal","sequence":"first","affiliation":[{"name":"Molecular Physiology Unit, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n and Instituto de Investigaciones Biom\u00e9dicas, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Tlalpan 14000 Mexico City, Mexico;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Pacheco-Alvarez","sequence":"additional","affiliation":[{"name":"Molecular Physiology Unit, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n and Instituto de Investigaciones Biom\u00e9dicas, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Tlalpan 14000 Mexico City, Mexico;"},{"name":"Escuela de Medicina, Universidad Panamericana, Mexico City, 03920 Mexico;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ciaran","family":"Richardson","sequence":"additional","affiliation":[{"name":"Medical Research Council Protein Phosphorylation Unit, MSI\/WTB complex, University of Dundee, Dow Street, Dundee, DD1 5EH, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron M.","family":"Ring","sequence":"additional","affiliation":[{"name":"Departments of Genetics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norma","family":"Vazquez","sequence":"additional","affiliation":[{"name":"Molecular Physiology Unit, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n and Instituto de Investigaciones Biom\u00e9dicas, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Tlalpan 14000 Mexico City, Mexico;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatema H.","family":"Rafiqi","sequence":"additional","affiliation":[{"name":"Medical Research Council Protein Phosphorylation Unit, MSI\/WTB complex, University of Dundee, Dow Street, Dundee, DD1 5EH, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Divya","family":"Chari","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Physiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristopher T.","family":"Kahle","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Leng","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Physiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norma A.","family":"Bobadilla","sequence":"additional","affiliation":[{"name":"Molecular Physiology Unit, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n and Instituto de Investigaciones Biom\u00e9dicas, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Tlalpan 14000 Mexico City, Mexico;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven C.","family":"Hebert","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Physiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510; 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