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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2019,2,19]]},"abstract":"<jats:title>Significance<\/jats:title>\n                  <jats:p>\n                    Calcineurin inhibitors (CNIs) are potent immunosuppressants; hypertension and hyperkalemia are common adverse effects. Activation of the renal Na-Cl cotransporter (NCC) is implicated in this toxicity; however, the mechanism is unknown. CNIs\u2019 renal effects mimic the hypertension and hyperkalemia resulting from mutations in WNK kinases or in KLHL3-CUL3 ubiquitin ligase. WNKs activate NCC and are degraded by ubiquitylation upon their binding to KLHL3. The binding of WNKs to KLHL3 is prevented by KLHL3 mutations or by PKC-mediated KLHL3 phosphorylation at serine 433. This work shows that calcineurin dephosphorylates KLHL3\n                    <jats:sup>S433<\/jats:sup>\n                    , promoting WNK4 degradation. Conversely, CNIs inhibit KLHL3\n                    <jats:sup>S433<\/jats:sup>\n                    dephosphorylation, preventing WNK degradation. These findings implicate calcineurin in the normal regulation of KLHL3\u2019s binding of WNK4 and identify a direct target causing CNI-induced pathology.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1817281116","type":"journal-article","created":{"date-parts":[[2019,2,4]],"date-time":"2019-02-04T20:43:28Z","timestamp":1549313008000},"page":"3155-3160","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":70,"title":["Calcineurin dephosphorylates Kelch-like 3, reversing phosphorylation by angiotensin II and regulating renal electrolyte handling"],"prefix":"10.1073","volume":"116","author":[{"given":"Kenichi","family":"Ishizawa","sequence":"first","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, 173-8605 Tokyo, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of 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