{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T19:06:06Z","timestamp":1790017566393,"version":"4.0.1"},"reference-count":71,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JASN"],"published-print":{"date-parts":[[2018,7]]},"abstract":"<jats:p>\n                    <jats:bold>Background<\/jats:bold>\n                    Hypercalciuria can result from activation of the basolateral calcium-sensing receptor (CaSR), which in the thick ascending limb of Henle\u2019s loop controls Ca\n                    <jats:sup>2+<\/jats:sup>\n                    excretion and NaCl reabsorption in response to extracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    . However, the function of CaSR in the regulation of NaCl reabsorption in the distal convoluted tubule (DCT) is unknown. We hypothesized that CaSR in this location is involved in activating the thiazide-sensitive NaCl cotransporter (NCC) to prevent NaCl loss.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Methods<\/jats:bold>\n                    We used a combination of\n                    <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                    models to examine the effects of CaSR on NCC activity. Because the KLHL3-WNK4-SPAK pathway is involved in regulating NaCl reabsorption in the DCT, we assessed the involvement of this pathway as well.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Results<\/jats:bold>\n                    Thiazide-sensitive\n                    <jats:sup>22<\/jats:sup>\n                    Na\n                    <jats:sup>+<\/jats:sup>\n                    uptake assays in\n                    <jats:italic toggle=\"yes\">Xenopus laevis<\/jats:italic>\n                    oocytes revealed that NCC activity increased in a WNK4-dependent manner upon activation of CaSR with Gd\n                    <jats:sup>3+<\/jats:sup>\n                    . In HEK293 cells, treatment with the calcimimetic R-568 stimulated SPAK phosphorylation only in the presence of WNK4. The WNK4 inhibitor WNK463 also prevented this effect. Furthermore, CaSR activation in HEK293 cells led to phosphorylation of KLHL3 and WNK4 and increased WNK4 abundance and activity. Finally, acute oral administration of R-568 in mice led to the phosphorylation of NCC.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Conclusions<\/jats:bold>\n                    Activation of CaSR can increase NCC activity\n                    <jats:italic toggle=\"yes\">via<\/jats:italic>\n                    the WNK4-SPAK pathway. It is possible that activation of CaSR by Ca\n                    <jats:sup>2+<\/jats:sup>\n                    in the apical membrane of the DCT increases NaCl reabsorption by NCC, with the consequent, well known decrease of Ca\n                    <jats:sup>2+<\/jats:sup>\n                    reabsorption, further promoting hypercalciuria.\n                  <\/jats:p>","DOI":"10.1681\/asn.2017111155","type":"journal-article","created":{"date-parts":[[2018,5,30]],"date-time":"2018-05-30T10:45:31Z","timestamp":1527677131000},"page":"1838-1848","source":"Crossref","is-referenced-by-count":45,"title":["The Calcium-Sensing Receptor Increases Activity of the Renal NCC through the WNK4-SPAK Pathway"],"prefix":"10.1681","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8907-3852","authenticated-orcid":false,"given":"Silvana","family":"Baz\u00faa-Valenti","sequence":"first","affiliation":[{"name":"Molecular Physiology Unit, Instituto de Investigaciones Biom\u00e9dicas, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Mexico City, Mexico;"},{"name":"Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Mexico City, Mexico;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorena","family":"Rojas-Vega","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Mexico City, Mexico;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Casta\u00f1eda-Bueno","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Mexico City, Mexico;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonatan","family":"Barrera-Chimal","sequence":"additional","affiliation":[{"name":"Molecular Physiology Unit, Instituto de Investigaciones Biom\u00e9dicas, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Mexico City, Mexico;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roc\u00edo","family":"Bautista","sequence":"additional","affiliation":[{"name":"Departments of Molecular Biology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luz G.","family":"Cervantes-P\u00e9rez","sequence":"additional","affiliation":[{"name":"Pharmacology, Instituto Nacional de Cardiolog\u00eda Ignacio Ch\u00e1vez, Mexico City, Mexico;"}],"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, Mexico City, Mexico;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Consuelo","family":"Plata","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Mexico City, Mexico;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adri\u00e1n R.","family":"Murillo-de-Ozores","sequence":"additional","affiliation":[{"name":"Molecular Physiology Unit, Instituto de Investigaciones Biom\u00e9dicas, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Mexico City, Mexico;"},{"name":"Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Mexico City, Mexico;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenza","family":"Gonz\u00e1lez-Mariscal","sequence":"additional","affiliation":[{"name":"Department of Physiology, Biophysics and Neuroscience, Center 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Physiology Unit, Instituto de Investigaciones Biom\u00e9dicas, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Mexico City, Mexico;"},{"name":"Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Mexico City, Mexico;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4378-9043","authenticated-orcid":false,"given":"Gerardo","family":"Gamba","sequence":"additional","affiliation":[{"name":"Molecular Physiology Unit, Instituto de Investigaciones Biom\u00e9dicas, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Mexico City, Mexico;"},{"name":"Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Mexico City, Mexico;"},{"name":"Tecnol\u00f3gico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Nuevo Le\u00f3n, 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