{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:11:14Z","timestamp":1790835074807,"version":"4.1.0"},"reference-count":76,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T00:00:00Z","timestamp":1672790400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>With-no-lysine (K) (WNK) kinases have been identified as the causal genes for pseudohypoaldosteronism type II (PHAII), a rare hereditary hypertension condition characterized by hyperkalemia, hyperchloremic metabolic acidosis, and thiazide-hypersensitivity. We thought that clarifying the link between WNK and NaCl cotransporter (NCC) would bring us new mechanism(s) of NCC regulation. For the first time, we were able to produce a knock-in mouse model of PHAII and anti-phosphorylated NCC antibodies against the putative NCC phosphorylation sites and discover that constitutive activation of NCC and increased phosphorylation of NCC are the primary pathogenesis of the disease <jats:italic>in vivo<\/jats:italic>. We have since demonstrated that this regulatory mechanism is mediated by the kinases oxidative stress-response protein 1 (OSR1) and STE20\/SPS1-related proline\/alanine-rich kinase (SPAK) (WNK\u2013OSR1\/SPAK-NCC signaling cascade) and that the signaling is not only important in the pathological condition of PHAII but also plays a crucial physiological role in the regulation of NCC.<\/jats:p>","DOI":"10.3389\/fphys.2022.1081261","type":"journal-article","created":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T13:09:26Z","timestamp":1672837766000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":20,"title":["NCC regulation by WNK signal cascade"],"prefix":"10.3389","volume":"13","author":[{"given":"Shinichi","family":"Uchida","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayasu","family":"Mori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichiro","family":"Susa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eisei","family":"Sohara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,1,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/s0962-8924(99)01673-6","article-title":"The kelch repeat superfamily of proteins: Propellers of cell function","volume":"10","author":"Adams","year":"2000","journal-title":"Trends Cell Biol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"2507","DOI":"10.1056\/NEJMoa2110730","article-title":"Chlorthalidone for hypertension in advanced chronic kidney disease","volume":"385","author":"Agarwal","year":"2021","journal-title":"N. 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