{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T01:35:53Z","timestamp":1793151353214,"version":"4.5.0"},"reference-count":41,"publisher":"American Physiological Society","issue":"3","funder":[{"name":"Conacyt Mexico","award":["188712"],"award-info":[{"award-number":["188712"]}]},{"name":"DGAPA-UNAM","award":["IN207716"],"award-info":[{"award-number":["IN207716"]}]},{"name":"NIDDK, NIH","award":["DK051496-15"],"award-info":[{"award-number":["DK051496-15"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Renal Physiology"],"published-print":{"date-parts":[[2018,9,1]]},"abstract":"<jats:p>Familial hyperkalemic hypertension (FHHt) can be mainly attributed to increased activity of the renal Na<jats:sup>+<\/jats:sup>:Cl<jats:sup>\u2212<\/jats:sup>cotransporter (NCC), which is caused by altered expression and regulation of the with-no-lysine (K) 1 (WNK1) or WNK4 kinases. The WNK1 gene gives rise to a kidney-specific isoform that lacks the kinase domain (KS-WNK1), the expression of which occurs primarily in the distal convoluted tubule. The role played by KS-WNK1 in the modulation of the WNK\/STE20-proline-alanine rich kinase (SPAK)\/NCC pathway remains elusive. In the present study, we assessed the effect of human KS-WNK1 on NCC activity and on the WNK4-SPAK pathway. Microinjection of oocytes with human KS-WNK1 cRNA induces remarkable activation and phosphorylation of SPAK and NCC. The effect of KS-WNK1 was abrogated by eliminating a WNK-WNK-interacting domain and by a specific WNK inhibitor, WNK463, indicating that the activation of SPAK\/NCC by KS-WNK1 is due to interaction with another WNK kinase. Under control conditions in oocytes, the activating serine 335 of the WNK4 T loop is not phosphorylated. In contrast, this serine becomes phosphorylated when the intracellular chloride concentration ([Cl<jats:sup>\u2212<\/jats:sup>]<jats:sub>i<\/jats:sub>) is reduced or when KS-WNK1 is coexpressed with WNK4. KS-WNK1-mediated activation of WNK4 is not due to a decrease of the [Cl<jats:sup>\u2212<\/jats:sup>]<jats:sub>i<\/jats:sub>. Coimmunoprecipitation analysis revealed that KS-WNK1 and WNK4 interact with each other and that WNK4 becomes autophosphorylated at serine 335 when it is associated with KS-WNK1. Together, these observations suggest that WNK4 becomes active in the presence of KS-WNK1, despite a constant [Cl<jats:sup>\u2212<\/jats:sup>]<jats:sub>i<\/jats:sub>.<\/jats:p>","DOI":"10.1152\/ajprenal.00145.2018","type":"journal-article","created":{"date-parts":[[2018,5,31]],"date-time":"2018-05-31T16:13:51Z","timestamp":1527783231000},"page":"F734-F745","source":"Crossref","is-referenced-by-count":61,"title":["Kidney-specific WNK1 isoform (KS-WNK1) is a potent activator of WNK4 and NCC"],"prefix":"10.1152","volume":"315","author":[{"given":"Eduardo R.","family":"Argaiz","sequence":"first","affiliation":[{"name":"Molecular Physiology Unit, Instituto de Investigaciones Biom\u00e9dicas, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Tlalpan, Mexico City, Mexico"},{"name":"Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Tlalpan Mexico City, Mexico"},{"name":"Tecnol\u00f3gico de Monterrey, Escuela de 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