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Mutations of ClC-Kb cause classic Bartter syndrome, characterized by renal salt wasting, with perinatal to adolescent onset. We studied the roles of Clc-k channels in perinatal mouse kidneys using constitutive or inducible kidney-specific gene ablation and 2D and advanced 3D imaging of optically cleared kidneys. We show that Clc-k1 and Clc-k2 were broadly expressed and colocalized in perinatal kidneys. Deletion of Clc-k1 and Clc-k2 revealed that both participated in NKCC2- and NCC-mediated NaCl reabsorption in neonatal kidneys. Embryonic deletion of Clc-k2 caused tubular injury and impaired renal medulla and TAL development. Inducible deletion of Clc-k2 beginning after medulla maturation produced mild salt wasting resulting from reduced NCC activity. Thus, both Clc-k1 and Clc-k2 contributed to salt reabsorption in TAL and distal convoluted tubule (DCT) in neonates, potentially explaining the less-severe phenotypes in classic Bartter syndrome. As opposed to the current understanding that salt wasting in adult patients with Bartter syndrome is due to Clc-k2 deficiency in adult TAL, our results suggest that it originates mainly from defects occurring in the medulla and TAL during development.<\/jats:p>","DOI":"10.1172\/jci.insight.151039","type":"journal-article","created":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T12:04:08Z","timestamp":1631189048000},"source":"Crossref","is-referenced-by-count":19,"title":["Impairment in renal medulla development underlies salt wasting in Clc-k2 channel deficiency"],"prefix":"10.1172","volume":"6","author":[{"given":"Meng-Hsuan","family":"Lin","sequence":"first","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Tri-Service General Hospital, and"},{"name":"Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jen-Chi","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Tri-Service General Hospital, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuejiao","family":"Tian","sequence":"additional","affiliation":[{"name":"Brain Research Center, National Tsing Hua University, Hsinchu, Taiwan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Ming","family":"Lee","sequence":"additional","affiliation":[{"name":"Research Center for Applied Sciences, Academia Sinica, Taipei, Taiwan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2369-5816","authenticated-orcid":true,"given":"I-Shing","family":"Yu","sequence":"additional","affiliation":[{"name":"Laboratory Animal Center, College of Medicine, National Taiwan University, Taipei, Taiwan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Fen","family":"Lo","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Tri-Service General Hospital, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinichi","family":"Uchida","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chou-Long","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1876-7432","authenticated-orcid":true,"given":"Bi-Chang","family":"Chen","sequence":"additional","affiliation":[{"name":"Brain Research Center, National Tsing Hua University, Hsinchu, Taiwan."},{"name":"Research Center for Applied Sciences, Academia Sinica, Taipei, Taiwan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6908-3428","authenticated-orcid":true,"given":"Chih-Jen","family":"Cheng","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Tri-Service General Hospital, and"},{"name":"Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan."},{"name":"Division of Nephrology, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2021,10,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1097-171"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1523-1755.2004.00363.x"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddm112"},{"issue":"2","key":"B4","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1016\/j.gene.2013.06.055","article-title":"A CLCNKA polymorphism (rs10927887; 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