{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T23:01:31Z","timestamp":1784070091596,"version":"3.55.0"},"reference-count":33,"publisher":"American Physiological Society","issue":"5","funder":[{"DOI":"10.13039\/100000062","name":"HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)","doi-asserted-by":"publisher","award":["DK109887"],"award-info":[{"award-number":["DK109887"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)","doi-asserted-by":"publisher","award":["DK100605"],"award-info":[{"award-number":["DK100605"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)","doi-asserted-by":"publisher","award":["DK111542"],"award-info":[{"award-number":["DK111542"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)","doi-asserted-by":"publisher","award":["and DK59530"],"award-info":[{"award-number":["and DK59530"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Renal Physiology"],"published-print":{"date-parts":[[2018,5,1]]},"abstract":"<jats:p> The Na<jats:sup>+<\/jats:sup>-Cl<jats:sup>\u2212<\/jats:sup> cotransporter (NCC) in distal convoluted tubule (DCT) plays important roles in renal NaCl reabsorption. The current hypothesis for the mechanism of regulation of NCC focuses on WNK4 and intracellular Cl<jats:sup>\u2212<\/jats:sup> concentration ([Cl<jats:sup>\u2212<\/jats:sup>]<jats:sub>i<\/jats:sub>). WNK kinases bind Cl<jats:sup>\u2212<\/jats:sup>, and Cl<jats:sup>\u2212<\/jats:sup> binding decreases the catalytic activity. It is believed that hypokalemia under low K<jats:sup>+<\/jats:sup> intake decreases [Cl<jats:sup>\u2212<\/jats:sup>]<jats:sub>i<\/jats:sub> to activate WNK4, which thereby phosphorylates and stimulates NCC through activation of SPAK. However, increased NCC activity and apical NaCl entry would mitigate the fall in [Cl<jats:sup>\u2212<\/jats:sup>]<jats:sub>i.<\/jats:sub> Whether [Cl<jats:sup>\u2212<\/jats:sup>]<jats:sub>i<\/jats:sub> in DCT under low-K<jats:sup>+<\/jats:sup> diet is sufficiently low to activate WNK4 is unknown. Furthermore, increased luminal NaCl delivery also stimulates NCC and causes upregulation of the transporter. Unlike low K<jats:sup>+<\/jats:sup> intake, increased luminal NaCl delivery would tend to increase [Cl<jats:sup>\u2212<\/jats:sup>]<jats:sub>i<\/jats:sub>. Thus we investigated the role of WNK4 and [Cl<jats:sup>\u2212<\/jats:sup>]<jats:sub>i<\/jats:sub> in regulating NCC. We generated Wnk4-knockout mice and examined regulation of NCC by low K<jats:sup>+<\/jats:sup> intake and by increased luminal NaCl delivery in knockout (KO) and wild-type mice. Wnk4-KO mice have marked reduction in the abundance, phosphorylation, and functional activity of NCC vs. wild type. Low K<jats:sup>+<\/jats:sup> intake increases NCC phosphorylation and functional activity in wild-type mice, but not in Wnk4-KO mice. Increased luminal NaCl delivery similarly upregulates NCC, which, contrary to low K<jats:sup>+<\/jats:sup> intake, is not abolished in Wnk4-KO mice. The results reveal that modulation of WNK4 activity by [Cl<jats:sup>\u2212<\/jats:sup>]<jats:sub>i<\/jats:sub> is not the sole mechanism for regulating NCC. Increased luminal NaCl delivery upregulates NCC via yet unknown mechanism(s) that may override inhibition of WNK4 by high [Cl<jats:sup>\u2212<\/jats:sup>]<jats:sub>i<\/jats:sub>. <\/jats:p>","DOI":"10.1152\/ajprenal.00177.2017","type":"journal-article","created":{"date-parts":[[2018,1,31]],"date-time":"2018-01-31T10:25:39Z","timestamp":1517394339000},"page":"F999-F1007","source":"Crossref","is-referenced-by-count":27,"title":["Differential roles of WNK4 in regulation of NCC in vivo"],"prefix":"10.1152","volume":"314","author":[{"given":"Yih-Sheng","family":"Yang","sequence":"first","affiliation":[{"name":"Division of Nephrology, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Xie","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung-Sen","family":"Yang","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Tri-Service General Hospital, and Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan"},{"name":"Graduate Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Hua","family":"Lin","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Tri-Service General Hospital, and Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chou-Long","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, 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