{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T20:45:01Z","timestamp":1750797901647},"reference-count":63,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2013,11,21]],"date-time":"2013-11-21T00:00:00Z","timestamp":1384992000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clin Exp Pharma Physio"],"published-print":{"date-parts":[[2013,12]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>\n<jats:list>\n\n<jats:list-item><jats:p>Human blood pressure is dependent on balancing dietary salt intake with its excretion by the kidney. Mendelian syndromes of altered blood pressure demonstrate the importance of the distal nephron in this process and of the thiazide\u2010sensitive pathway in particular.<\/jats:p><\/jats:list-item>\n\n<jats:list-item><jats:p>Gordon syndrome (<jats:styled-content style=\"fixed-case\">GS<\/jats:styled-content>), the phenotypic inverse of the salt\u2010wasting Gitelman syndrome, is a condition of hyperkalaemic hypertension that is reversed by low\u2010dose thiazide diuretics or a low\u2010salt diet. Variants within at least four genes [i.e. with\u2010no\u2010lysine(K) kinase 1 (<jats:styled-content style=\"fixed-case\"><jats:italic>WNK1<\/jats:italic><\/jats:styled-content>), <jats:styled-content style=\"fixed-case\"><jats:italic>WNK4<\/jats:italic><\/jats:styled-content>, kelch\u2010like family member 3 (<jats:styled-content style=\"fixed-case\"><jats:italic>KLHL3<\/jats:italic><\/jats:styled-content>) and cullin 3 (<jats:styled-content style=\"fixed-case\"><jats:italic>CUL3<\/jats:italic><\/jats:styled-content>)] can cause the phenotype of <jats:styled-content style=\"fixed-case\">GS<\/jats:styled-content>. Details are still emerging for some of these genes, but it is likely that they all cause a gain\u2010of\u2010function in the thiazide\u2010sensitive Na<jats:sup>+<\/jats:sup>\u2013Cl<jats:sup>\u2212<\/jats:sup> cotransporter (<jats:styled-content style=\"fixed-case\">NCC<\/jats:styled-content>) and hence salt retention. Herein, we discuss the key role of <jats:styled-content style=\"fixed-case\">STE<\/jats:styled-content>20\/sporulation\u2010specific protein 1 (<jats:styled-content style=\"fixed-case\">SPS<\/jats:styled-content>1)\u2010related proline\/alanine\u2010rich kinase (<jats:styled-content style=\"fixed-case\">SPAK<\/jats:styled-content>), which functions as an intermediary between the <jats:styled-content style=\"fixed-case\">WNK<\/jats:styled-content>s and <jats:styled-content style=\"fixed-case\">NCC<\/jats:styled-content> and for which a loss\u2010of\u2010function mutation produces a Gitelman\u2010type phenotype in a mouse model.<\/jats:p><\/jats:list-item>\n\n<jats:list-item><jats:p>In addition to Mendelian blood pressure syndromes, the study of patients who develop thiazide\u2010induced\u2010hyponatraemia (<jats:styled-content style=\"fixed-case\">TIH<\/jats:styled-content>) may give further molecular insights into the role of the thiazide\u2010sensitive pathway for salt reabsorption. In the present paper we discuss the key features of <jats:styled-content style=\"fixed-case\">TIH<\/jats:styled-content>, including its high degree of reproducibility on rechallenge, possible genetic predisposition and mechanisms involving excessive saliuresis and water retention.<\/jats:p><\/jats:list-item>\n\n<jats:list-item><jats:p>Together, studies of Gordon syndrome and <jats:styled-content style=\"fixed-case\">TIH<\/jats:styled-content> may increase our understanding of the molecular regulation of sodium trafficking via the thiazide\u2010sensitive pathway and have important implications for hypertensive patients, both in the identification of new antihypertensive drug targets and avoidance of hyponatraemic side\u2010effects.<\/jats:p><\/jats:list-item>\n<\/jats:list>\n<\/jats:p>","DOI":"10.1111\/1440-1681.12115","type":"journal-article","created":{"date-parts":[[2013,5,18]],"date-time":"2013-05-18T08:07:03Z","timestamp":1368864423000},"page":"876-884","source":"Crossref","is-referenced-by-count":17,"title":["Molecular insights from dysregulation of the thiazide\u2010sensitive <scp>WNK<\/scp>\/<scp>SPAK<\/scp>\/<scp>NCC<\/scp> pathway in the kidney: Gordon syndrome and thiazide\u2010induced hyponatraemia"],"prefix":"10.1111","volume":"40","author":[{"given":"Mark","family":"Glover","sequence":"first","affiliation":[{"name":"Division of Therapeutics and Molecular Medicine University of Nottingham Nottingham UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin M","family":"O'Shaughnessy","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Unit Department of Medicine University of Cambridge Cambridge UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2013,11,21]]},"reference":[{"key":"e_1_2_9_2_1","unstructured":"National Institute for Health and Care Excellence (NICE).Hypertension: clinical management of primary hypertension in adults. 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