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Although\n                    <jats:italic>\n                      Klhl3\n                      <jats:sup>R528H<\/jats:sup>\n                    <\/jats:italic>\n                    <jats:sup>\/+<\/jats:sup>\n                    knock\u2010in (KI) mice carrying a missense mutation in the Kelch repeat domain have been reported, nonsense\n                    <jats:italic>KLHL3<\/jats:italic>\n                    \u00a0mutations in the same domain that cause PHAII have not been fully investigated in vivo. We generated and analyzed\n                    <jats:italic>Klhl3<\/jats:italic>\n                    \u00a0KI mice harboring a nonsense\n                    <jats:italic>W523X<\/jats:italic>\n                    mutation (corresponding to the human\n                    <jats:italic>KLHL3<\/jats:italic>\n                    \u00a0W470X mutation). Both heterozygous and homozygous\n                    <jats:italic>\n                      Klhl3\n                      <jats:sup>W523X<\/jats:sup>\n                    <\/jats:italic>\n                    <jats:sup>\/+<\/jats:sup>\n                    KI mice exhibited typical PHAII with low\u2010renin hypertension, hyperkalemia with reduced renal potassium excretion, and hyperchloremic metabolic acidosis. Their kidney tissues showed the presence of\n                    <jats:italic>Klhl3<\/jats:italic>\n                    \u00a0mRNA and increased Klhl3 protein levels along with enhanced downstream Wnk1\/4\u2010Spak\/Osr1\u2010N(k)cc phosphorylation. Increased protein expression of total Spak, phosphor(p\u2010)Spak, total Ncc, and p\u2010Ncc from urinary extracellular vesicles (uEVs) also confirmed the activation of the Wnk\u2010mediated Ncc pathway. In vitro studies showed that the human\n                    <jats:italic>KLHL3<\/jats:italic>\n                    \u00a0W470X mutation resulted in increased KLHL3 protein stability and disrupted its binding affinity for WNK1\/4, leading to the attenuated degradation and increased abundance of total WNKs. In conclusion, nonsense\n                    <jats:italic>\n                      Klhl3\n                      <jats:sup>W523X<\/jats:sup>\n                    <\/jats:italic>\n                    <jats:sup>\/+<\/jats:sup>\n                    mice recapitulating PHAII phenotypes exhibit Klhl3 protein stability, abrogating its binding to Wnks, with enhanced Ncc expression in the kidney tissue and even in uEVs. Activation of the WNK\u2010mediated Na\n                    <jats:sup>+<\/jats:sup>\n                    \u2010Cl\n                    <jats:sup>\u2212<\/jats:sup>\n                    co\u2010transporter reiterated the in vivo pathogenic role of nonsense\n                    <jats:italic>KLHL3<\/jats:italic>\n                    \u00a0mutations in PHAII.\n                  <\/jats:p>","DOI":"10.1096\/fj.202101827rr","type":"journal-article","created":{"date-parts":[[2022,5,27]],"date-time":"2022-05-27T09:55:11Z","timestamp":1653645311000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Generation and analysis of pseudohypoaldosteronism type II knock\u2010in mice caused by a nonsense KLHL3 mutation in the Kelch domain"],"prefix":"10.1096","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7525-5743","authenticated-orcid":false,"given":"Chien\u2010Ming","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Pediatrics Tri\u2010Service General Hospital National Defense Medical Center  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih\u2010Chien","family":"Sung","sequence":"additional","affiliation":[{"name":"Division of Nephrology Department of Medicine Tri\u2010Service General Hospital National Defense Medical Center  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung\u2010Sen","family":"Yang","sequence":"additional","affiliation":[{"name":"Division of Nephrology Department of Medicine Tri\u2010Service General Hospital National Defense Medical Center  Taipei Taiwan"},{"name":"Graduate Institute of Medical Sciences National Defense Medical Center  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying\u2010Chuan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Physiology &amp; Biophysics National Defense Medical Center  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih\u2010Ming","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry National Defense Medical Center  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih\u2010Hua","family":"Lin","sequence":"additional","affiliation":[{"name":"Division of Nephrology Department of Medicine Tri\u2010Service General Hospital National Defense Medical Center  Taipei Taiwan"},{"name":"Graduate Institute of Medical Sciences National Defense Medical Center  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,5,27]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2009-0951"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2013.05.013"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00440.2013"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2005030314"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10814"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2218"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.084111"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2007.03.009"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.111.172429"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1304230110"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1200947109"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.200900058"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2009121295"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1042\/BSR20140047"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1062844"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21364"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1107452108"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2013.02.024"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu217"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00358.2009"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.402800"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20111879"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1097\/MNH.0b013e32830dd580"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2017.01.007"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20121903"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2013.04.032"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1304592110"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2016.10.127"},{"key":"e_1_2_10_30_1","volume-title":"Pseudohypoaldosteronism Type II. 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