{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:33:13Z","timestamp":1792787593370,"version":"4.5.0"},"reference-count":34,"publisher":"American Society for Clinical Investigation","issue":"19","license":[{"start":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000},"content-version":"vor","delay-in-days":49,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health, U.S.A","award":["DK134420"],"award-info":[{"award-number":["DK134420"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institutes of Health, U.S.A.","award":["DK111542"],"award-info":[{"award-number":["DK111542"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,8]]},"abstract":"<jats:p>\n                    The pathogenesis of Bartter syndrome (BS) has long been attributed to decreased salt reabsorption in the thick ascending limb of Henle\u2019s loop (TAL). By studying Clc-k2\u2013KO (mouse ortholog of ClC-Kb\u2013KO [Clc-k2\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    ]) mice, we recently uncovered an additional mechanism in which loss of Clc-k2 induces TAL hypoplasia in neonatal kidneys, exacerbating BS severity. Here, we further investigated this mechanism. TALs and distal convoluted tubules (DCTs) isolated from Clc-k2\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    and WT mice were used for transcriptome, proteomics, cell cycle, and proliferation assays. Mitochondrial morphology and function were studied using electron microscopy and mitochondrial respiration assays. Our results reveal impairments in cell proliferation, S-to-G2\/M cell cycle transition, mitochondrial biogenesis, oxidative phosphorylation, glycolysis, and fatty acid oxidation in Clc-k2\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    TALs and DCTs. Increasing transport function by introducing a gain-of-function with-no-lysine kinase 4 (Wnk4) mutation in Clc-k2\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    mice restored these metabolic and proliferative impairments and improved phenotype. Transgenic expression of peroxisome proliferator-activated receptor \u03b3 coactivator-1\u03b1, a master regulator of mitochondrial biogenesis, in Clc-k2\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    mice also alleviated mitochondrial dysfunction and phenotype. These findings support the hypothesis that mitochondrial hypofunction, resulting from decreased transport function, contributes to cell cycle arrest and tubular hypoplasia in BS. Targeting mitochondria early in life could be a therapeutic approach for BS.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.201067","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T16:00:37Z","timestamp":1787241637000},"source":"Crossref","is-referenced-by-count":0,"title":["Mitochondrial dysfunction underlies cell cycle arrest and tubular hypoplasia in ClC-Kb\u2013deficient Bartter syndrome mice"],"prefix":"10.1172","volume":"11","author":[{"given":"Chiao-Hui","family":"Hsieh","sequence":"first","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"}]},{"given":"Yu-Jen","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA."},{"name":"Division of 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