{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T16:21:27Z","timestamp":1773418887867,"version":"3.50.1"},"reference-count":26,"publisher":"Portland Press Ltd.","issue":"12","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2013,6,1]]},"abstract":"<jats:p>Mutations in the novel serine\/threonine WNK [With No lysine (=K)] kinases WNK1 and WNK4 cause PHAII (pseudohypoaldosteronism type\u00a0II or Gordon's syndrome), a rare monogenic syndrome which causes hypertension and hyperkalaemia on a background of a normal glomerular filtration rate. Current animal models for PHAII recapitulate some aspects of the disease phenotype, but give no clues to how rapidly the phenotype emerges or whether it is reversible. To this end we have created an inducible PHAII transgenic animal model that expresses a human disease-causing WNK4 mutation, WNK4 Q565E, under the control of the Tet-On system. Several PHAII inducible transgenic mouse lines were created, each with differing TG (transgene) copy numbers and displaying varying degrees of TG expression (low, medium and high). Each of these transgenic lines demonstrated similar elevations of BP (blood pressure) and plasma potassium after 4\u00a0weeks of TG induction. Withdrawal of doxycycline switched off mutant TG expression and the disappearance of the PHAII phenotype. Western blotting of microdissected kidney nephron segments confirmed that expression of the thiazide-sensitive NCC (Na+\u2013Cl\u2212 co-transporter) was increased, as expected, in the distal convoluted tubule when transgenic mice were induced with doxycycline. The kidneys of these mice also do not show the morphological changes seen in the previous transgenic model expressing the same mutant form of WNK4. This inducible model shows, for the first time, that in\u00a0vivo expression of a mutant WNK4 protein is sufficient to cause the rapid and reversible appearance of a PHAII disease phenotype in mice.<\/jats:p>","DOI":"10.1042\/cs20120430","type":"journal-article","created":{"date-parts":[[2013,1,23]],"date-time":"2013-01-23T06:19:16Z","timestamp":1358921956000},"page":"701-710","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["An inducible transgenic mouse model for familial hypertension with hyperkalaemia (Gordon's syndrome or pseudohypoaldosteronism type\u00a0II)"],"prefix":"10.1042","volume":"124","author":[{"given":"Jabed\u00a0A.","family":"Chowdhury","sequence":"first","affiliation":[{"name":"Clinical Pharmacology Unit, Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QQ, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Che-Hsiung","family":"Liu","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Unit, Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QQ, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annie\u00a0M.","family":"Zuber","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Unit, Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QQ, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin\u00a0M.","family":"O\u2019Shaughnessy","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Unit, Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QQ, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2013,2,26]]},"reference":[{"key":"2021113010242336200_B1","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1126\/science.1062844","article-title":"Human hypertension caused by mutations in WNK kinases","volume":"293","author":"Wilson","year":"2001","journal-title":"Science"},{"key":"2021113010242336200_B2","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1146\/annurev.physiol.70.113006.100651","article-title":"Molecular Physiology of the WNK Kinases","volume":"70","author":"Kahle","year":"2008","journal-title":"Annu. Rev. Physiol."},{"key":"2021113010242336200_B3","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1038\/nature10814","article-title":"Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities","volume":"482","author":"Boyden","year":"2012","journal-title":"Nature"},{"key":"2021113010242336200_B4","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1177\/003693308603100114","article-title":"The syndrome of hypertension and hyperkalaemia without renal failure: long term correction by thiazide diuretic","volume":"31","author":"Gordon","year":"1986","journal-title":"Scott. Med. J."},{"key":"2021113010242336200_B5","doi-asserted-by":"crossref","first-page":"3248","DOI":"10.1210\/jcem.87.7.8449","article-title":"Pseudohypoaldosteronism Type\u00a0II: marked sensitivity to Thiazides, Hypercalciuria, Normomagnesemia, and low bone mineral density","volume":"87","author":"Mayan","year":"2002","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2021113010242336200_B6","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1038\/ng1877","article-title":"Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule","volume":"38","author":"Lalioti","year":"2006","journal-title":"Nat. Genet."},{"key":"2021113010242336200_B7","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.cmet.2007.03.009","article-title":"Molecular pathogenesis of pseudohypoaldosteronism type\u00a0II: generation and analysis of a Wnk4D561A\/+knockin mouse model","volume":"5","author":"Yang","year":"2007","journal-title":"Cell Metab."},{"key":"2021113010242336200_B8","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1016\/j.bbrc.2005.04.169","article-title":"Apical localization of renal K channel was not altered in mutant WNK4 transgenic mice","volume":"332","author":"Yamauchi","year":"2005","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2021113010242336200_B9","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1161\/HYPERTENSIONAHA.110.167809","article-title":"Overexpression of the sodium chloride cotransporter is not sufficient to cause familial hyperkalemic hypertension","volume":"58","author":"McCormick","year":"2011","journal-title":"Hypertension"},{"key":"2021113010242336200_B10","doi-asserted-by":"crossref","first-page":"5547","DOI":"10.1073\/pnas.89.12.5547","article-title":"Tight control of gene expression in mammalian cells by tetracycline-responsive promoters","volume":"89","author":"Gossen","year":"1992","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021113010242336200_B11","doi-asserted-by":"crossref","first-page":"1766","DOI":"10.1126\/science.7792603","article-title":"Transcriptional activation by tetracyclines in mammalian cells","volume":"268","author":"Gossen","year":"1995","journal-title":"Science"},{"key":"2021113010242336200_B12","doi-asserted-by":"crossref","first-page":"10933","DOI":"10.1073\/pnas.93.20.10933","article-title":"Doxycycline-mediated quantitative and tissue-specific control of gene expression in transgenic mice","volume":"93","author":"Kistner","year":"1996","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021113010242336200_B13","journal-title":"Reference deleted"},{"key":"2021113010242336200_B14","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1038\/74914","article-title":"Transgenic expression of green fluorescence protein can cause dilated cardiomyopathy","volume":"6","author":"Huang","year":"2000","journal-title":"Nat. Med."},{"key":"2021113010242336200_B15","volume-title":"Manipulating the Mouse Embryo: A Laboratory Manual","author":"Hogan","year":"1994"},{"key":"2021113010242336200_B16","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/0076-6879(83)01031-9","article-title":"Gene transfer into mouse embryos: production of transgenic mice by pronuclear injection","volume":"101","author":"Gordon","year":"1983","journal-title":"Methods Enzymol."},{"key":"2021113010242336200_B17","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1002\/emmm.200900058","article-title":"Role of the WNK-activated SPAK kinase in regulating blood pressure","volume":"2","author":"Rafiqi","year":"2010","journal-title":"EMBO Mol. Med."},{"key":"2021113010242336200_B18","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1126\/science.1193004","article-title":"PiggyBac transposon mutagenesis: a tool for cancer gene discovery in mice","volume":"330","author":"Rad","year":"2010","journal-title":"Science"},{"key":"2021113010242336200_B19","doi-asserted-by":"crossref","first-page":"1530","DOI":"10.1073\/pnas.68.7.1530","article-title":"Identification of the mouse karyotype by quinacrine fluorescence, and tentative assignment of seven linkage groups","volume":"68","author":"Miller","year":"1971","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021113010242336200_B20","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1006\/geno.1997.4904","article-title":"FISH Probes for mouse chromosome identification","volume":"45","author":"Shi","year":"1997","journal-title":"Genomics"},{"key":"2021113010242336200_B21","doi-asserted-by":"crossref","first-page":"18109","DOI":"10.1073\/pnas.1006128107","article-title":"Decreased ENaC expression compensates the increased NCC activity following inactivation of the kidney-specific isoform of WNK1 and prevents hypertension","volume":"107","author":"Hadchouel","year":"2010","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021113010242336200_B22","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1093\/ndt\/gfq612","article-title":"Effect of age and affection status on blood pressure, serum potassium and stature in familial hyperkalaemia and hypertension","volume":"26","author":"Farfel","year":"2011","journal-title":"Nephrol. Dial. Transplant."},{"key":"2021113010242336200_B23","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1097\/MNH.0b013e3283484b06","article-title":"Role of SPAK and OSR1 signalling in the regulation of NaCl cotransporters","volume":"20","author":"Mercier-Zuber","year":"2011","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"2021113010242336200_B24","doi-asserted-by":"crossref","first-page":"18471","DOI":"10.1074\/jbc.M109.008185","article-title":"WNK4 diverts the thiazide-sensitive NaCl cotransporter to the lysosome and stimulates AP-3 interaction","volume":"284","author":"Subramanya","year":"2009","journal-title":"J. Biol. Chem."},{"key":"2021113010242336200_B25","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1242\/jcs.025312","article-title":"Activation of the thiazide-sensitive Na+-Cl\u2212 cotransporter by the WNK-regulated kinases SPAK and OSR1","volume":"121","author":"Richardson","year":"2008","journal-title":"J. Cell Sci."},{"key":"2021113010242336200_B26","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1161\/01.HYP.0000174326.96918.d6","article-title":"A new kindred with Pseudohypoaldosteronism Type\u00a0II and a novel mutation (564D&gt;H) in the acidic motif of the WNK4 gene","volume":"46","author":"Golbang","year":"2005","journal-title":"Hypertension"}],"container-title":["Clinical Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/124\/12\/701\/443320\/cs1240701.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/124\/12\/701\/443320\/cs1240701.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T05:53:54Z","timestamp":1638251634000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/clinsci\/article\/124\/12\/701\/69051\/An-inducible-transgenic-mouse-model-for-familial"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,2,26]]},"references-count":26,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2013,6,1]]}},"URL":"https:\/\/doi.org\/10.1042\/cs20120430","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.717982874.793472051","asserted-by":"object"}]},"ISSN":["0143-5221","1470-8736"],"issn-type":[{"value":"0143-5221","type":"print"},{"value":"1470-8736","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,2,26]]}}}