{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T20:54:16Z","timestamp":1793134456746,"version":"4.5.0"},"reference-count":60,"publisher":"National Academy of Sciences","issue":"43","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2014,10,28]]},"abstract":"<jats:title>Significance<\/jats:title>\n                  <jats:p>\n                    Aldosterone produces distinct adaptive responses in volume depletion and hyperkalemia. Mutations in with-no-lysine (WNK) kinases or ubiquitin ligases containing Cullin 3 (CUL3) and Kelch-like 3 (KLHL3) cause a Mendelian disease featuring hypertension and hyperkalemia due to constitutive renal salt reabsorption and inhibited K\n                    <jats:sup>+<\/jats:sup>\n                    secretion. WNKs modulate activities of aldosterone-regulated electrolyte flux pathways, and WNK levels are regulated by CUL3\/KLHL3; disease-causing mutations prevent WNK degradation. This manuscript shows that angiotensin II (AII), a hormone produced only in volume depletion, induces PKC-mediated phosphorylation of KLHL3, preventing WNK degradation and phenocopying KLHL3 mutations. These findings provide a mechanism by which AII signaling alters WNK4, promoting increased renal salt reabsorption and reduced K\n                    <jats:sup>+<\/jats:sup>\n                    secretion.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1418342111","type":"journal-article","created":{"date-parts":[[2014,10,14]],"date-time":"2014-10-14T00:00:15Z","timestamp":1413244815000},"page":"15556-15561","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":102,"title":["Angiotensin II signaling via protein kinase C phosphorylates Kelch-like 3, preventing WNK4 degradation"],"prefix":"10.1073","volume":"111","author":[{"given":"Shigeru","family":"Shibata","sequence":"first","affiliation":[{"name":"Departments of aGenetics and"},{"name":"Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510;"},{"name":"Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo 173-8605, Japan; and"},{"name":"Department of Clinical Epigenetics, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-0041, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Pablo","family":"Arroyo","sequence":"additional","affiliation":[{"name":"Departments of aGenetics and"},{"name":"Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Casta\u00f1eda-Bueno","sequence":"additional","affiliation":[{"name":"Departments of aGenetics and"},{"name":"Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy","family":"Puthumana","sequence":"additional","affiliation":[{"name":"Departments of aGenetics and"},{"name":"Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junhui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Departments of aGenetics and"},{"name":"Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunya","family":"Uchida","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo 173-8605, Japan; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn L.","family":"Stone","sequence":"additional","affiliation":[{"name":"Molecular Biophysics and Biochemistry and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"TuKiet T.","family":"Lam","sequence":"additional","affiliation":[{"name":"Molecular Biophysics and Biochemistry and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard P.","family":"Lifton","sequence":"additional","affiliation":[{"name":"Departments of aGenetics and"},{"name":"Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2014,10,13]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00241-0"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1062844"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1198785"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10814"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200101043440101"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1311989"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.physiol.70.113006.100651"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00030.2003"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.V1271335"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI31538"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00582642"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.90475.2008"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semnephrol.2013.04.002"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2013.10.005"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1202671109"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1271"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.242735399"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI17443"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0406172101"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1877"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0611728104"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20121903"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1304592110"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2013.02.024"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7601243"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2218"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0813238106"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1200947109"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1305242110"},{"key":"e_1_3_3_30_2","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/S0031-6997(24)01458-3","article-title":"International union of pharmacology. XXIII. The angiotensin II receptors","volume":"52","author":"de Gasparo M","year":"2000","unstructured":"M de Gasparo, KJ Catt, T Inagami, JW Wright, T Unger, International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev 52, 415\u2013472 (2000).","journal-title":"Pharmacol Rev"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.1159433"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1210\/mend.11.9.9975"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1995.269.1.C134"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/0303-7207(94)90219-4"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.23.6.848"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.19.8.5289"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1007\/s002329900325"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2005111197"},{"key":"e_1_3_3_39_2","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/S0031-6997(25)00446-6","article-title":"Angiotensin II receptors and angiotensin II receptor antagonists","volume":"45","author":"Timmermans PB","year":"1993","unstructured":"PB Timmermans, , Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev 45, 205\u2013251 (1993).","journal-title":"Pharmacol Rev"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI112293"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2011.03.001"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2010.290"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.298919"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI65460"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M607477200"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI23378"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1210\/me.2005-0193"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1099414"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2013.06.104"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.10.7.2361"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.05.031"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600812"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1743"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature08011"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2013.52"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2337"},{"key":"e_1_3_3_57_2","first-page":"F432","article-title":"NaCl transport in mouse medullary thick ascending limbs. II. ADH enhancement of transcellular NaCl cotransport; origin of transepithelial voltage","volume":"241","author":"Hebert SC","year":"1981","unstructured":"SC Hebert, RM Culpepper, TE Andreoli, NaCl transport in mouse medullary thick ascending limbs. II. ADH enhancement of transcellular NaCl cotransport; origin of transepithelial voltage. Am J Physiol 241, F432\u2013F442 (1981).","journal-title":"Am J Physiol"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00019.2012"},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(00)80469-4"},{"key":"e_1_3_3_60_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biolcel.2003.09.001"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1418342111","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,4]],"date-time":"2025-05-04T23:56:03Z","timestamp":1746402963000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1418342111"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,10,13]]},"references-count":60,"journal-issue":{"issue":"43","published-print":{"date-parts":[[2014,10,28]]}},"alternative-id":["10.1073\/pnas.1418342111"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1418342111","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,10,13]]},"assertion":[{"value":"2014-10-13","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}