{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:45:14Z","timestamp":1790189114345,"version":"4.1.0"},"reference-count":73,"publisher":"Wiley","issue":"17","license":[{"start":{"date-parts":[[2016,5,29]],"date-time":"2016-05-29T00:00:00Z","timestamp":1464480000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2016,9]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>STE20 (Sterile 20)\/SPS\u20101 related proline\/alanine\u2010rich kinase (SPAK) and oxidative stress\u2010response kinase\u20101 (OSR1) phosphorylate and activate the renal Na<jats:sup>+<\/jats:sup>\u2013K<jats:sup>+<\/jats:sup>\u20132Cl<jats:sup>\u2212<\/jats:sup> cotransporter 2 (NKCC2) and Na<jats:sup>+<\/jats:sup>Cl<jats:sup>\u2212<\/jats:sup> cotransporter (NCC).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Mouse models suggest that OSR1 mainly activates NKCC2\u2010mediated sodium transport along the thick ascending limb, while SPAK mainly activates NCC along the distal convoluted tubule, but the kinases may compensate for each other. We hypothesized that disruption of both kinases would lead to polyuria and severe salt\u2010wasting, and generated SPAK\/OSR1 double knockout mice to test this.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Despite a lack of SPAK and OSR1, phosphorylated NKCC2 abundance was still high, suggesting the existence of an alternative activating kinase.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Compensatory changes in SPAK\/OSR1\u2010independent phosphorylation sites on both NKCC2 and NCC and changes in sodium transport along the collecting duct were also observed.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Potassium restriction revealed that SPAK and OSR1 play essential roles in the emerging model that NCC activation is central to sensing changes in plasma [K<jats:sup>+<\/jats:sup>].<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>STE20 (Sterile 20)\/SPS\u20101 related proline\/alanine\u2010rich kinase (SPAK) and oxidative stress\u2010response kinase\u20101 (OSR1) activate the renal cation cotransporters Na<jats:sup>+<\/jats:sup>\u2013K<jats:sup>+<\/jats:sup>\u20132Cl<jats:sup>\u2212<\/jats:sup> cotransporter (NKCC2) and Na<jats:sup>+<\/jats:sup>\u2013Cl<jats:sup>\u2212<\/jats:sup> cotransporter (NCC) via phosphorylation. Knockout mouse models suggest that OSR1 mainly activates NKCC2, while SPAK mainly activates NCC, with possible cross\u2010compensation. We tested the hypothesis that disrupting both kinases causes severe polyuria and salt\u2010wasting by generating SPAK\/OSR1 double knockout (DKO) mice. DKO mice displayed lower systolic blood pressure compared with SPAK knockout (SPAK\u2010KO) mice, but displayed no severe phenotype even after dietary salt restriction. Phosphorylation of NKCC2 at SPAK\/OSR1\u2010dependent sites was lower than in SPAK\u2010KO mice, but still significantly greater than in wild type mice. In the renal medulla, there was significant phosphorylation of NKCC2 at SPAK\/OSR1\u2010dependent sites despite a complete absence of SPAK and OSR1, suggesting the existence of an alternative activating kinase. The distal convoluted tubule has been proposed to sense plasma [K<jats:sup>+<\/jats:sup>], with NCC activation serving as the primary effector pathway that modulates K<jats:sup>+<\/jats:sup> secretion, by metering sodium delivery to the collecting duct. Abundance of phosphorylated NCC (pNCC) is dramatically lower in SPAK\u2010KO mice than in wild type mice, and the additional disruption of OSR1 further reduced pNCC. SPAK\u2010KO and kidney\u2010specific OSR1 single knockout mice maintained plasma [K<jats:sup>+<\/jats:sup>] following dietary potassium restriction, but DKO mice developed severe hypokalaemia. Unlike mice lacking SPAK or OSR1 alone, DKO mice displayed an inability to phosphorylate NCC under these conditions. These data suggest that SPAK and OSR1 are essential components of the effector pathway that maintains plasma [K<jats:sup>+<\/jats:sup>].<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp272311","type":"journal-article","created":{"date-parts":[[2016,4,12]],"date-time":"2016-04-12T09:17:19Z","timestamp":1460452639000},"page":"4945-4966","source":"Crossref","is-referenced-by-count":56,"title":["SPAK and OSR1 play essential roles in potassium homeostasis through actions on the distal convoluted tubule"],"prefix":"10.1113","volume":"594","author":[{"given":"Mohammed Z.","family":"Ferdaus","sequence":"first","affiliation":[{"name":"Division of Nephrology &amp; Hypertension Department of Medicine Oregon Health &amp; Science University  Portland OR 97239 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl W.","family":"Barber","sequence":"additional","affiliation":[{"name":"Department of Cellular &amp; Molecular Physiology Yale University  New Haven CT 06520 USA"},{"name":"Systems Biology Institute Yale University  Orange CT 06477 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9745-0774","authenticated-orcid":false,"given":"Karen I.","family":"L\u00f3pez\u2010Cayuqueo","sequence":"additional","affiliation":[{"name":"INSERM U970 Paris Cardiovascular Research Center Universit\u00e9 Paris\u2010Descartes  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew S.","family":"Terker","sequence":"additional","affiliation":[{"name":"Division of Nephrology &amp; Hypertension Department of Medicine Oregon Health &amp; Science University  Portland OR 97239 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo R.","family":"Argaiz","sequence":"additional","affiliation":[{"name":"Molecular Physiology Unit Instituto de Investigaciones Biom\u00e9dicas Universidad Nacional Aut\u00f3noma de M\u00e9xico and Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n  Mexico City Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon M.","family":"Gassaway","sequence":"additional","affiliation":[{"name":"Department of Cellular &amp; Molecular Physiology Yale University  New Haven CT 06520 USA"},{"name":"Systems Biology Institute Yale University  Orange CT 06477 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R\u00e9gine","family":"Chambrey","sequence":"additional","affiliation":[{"name":"INSERM U970 Paris Cardiovascular Research Center Universit\u00e9 Paris\u2010Descartes  Paris France"}],"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 and Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n  Mexico City 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