{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T16:12:16Z","timestamp":1791821536678,"version":"4.3.4"},"reference-count":105,"publisher":"American Society for Clinical Investigation","issue":"20","license":[{"start":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T00:00:00Z","timestamp":1761696000000},"content-version":"vor","delay-in-days":7,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institute of Health Research","doi-asserted-by":"crossref","award":["159727"],"award-info":[{"award-number":["159727"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]},{"name":"U.S. Department of Defense","award":["PR171055"],"award-info":[{"award-number":["PR171055"]}]},{"name":"Polycystic Kidney Disease Foundation USA","award":["197G14a"],"award-info":[{"award-number":["197G14a"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,10,22]]},"abstract":"<jats:p>\n                    The mechanisms underlying cyst growth and progression in Autosomal Dominant Polycystic Kidney Disease (ADPKD) remain unresolved. Since cyst expansion requires epithelial salt and water secretion likely involving basolateral membrane K\n                    <jats:sup>+<\/jats:sup>\n                    recycling, we investigated the role of\n                    <jats:italic>KCNN4<\/jats:italic>\n                    -encoded K\n                    <jats:sup>+<\/jats:sup>\n                    channel KCa3.1, inhibited by the potent, pharmacospecific, well-tolerated antagonist, senicapoc. We hypothesized that genetic and\/or pharmacological inactivation of\n                    <jats:italic>KCNN4<\/jats:italic>\n                    \/KCa3.1 would slow PKD progression.\n                    <jats:italic>KCNN4<\/jats:italic>\n                    was upregulated in kidneys of patients with ADPKD and of mechanistically distinct PKD mouse models. Cyst expansion in\n                    <jats:italic>\n                      Pkd1\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    murine metanephroi was stimulated by KCa3.1 agonist and was prevented\/reversed by senicapoc. In rapidly and\/or slowly progressive mouse\n                    <jats:italic>Pkd1<\/jats:italic>\n                    models,\n                    <jats:italic>Kcnn4<\/jats:italic>\n                    inactivation slowed renal cyst growth; attenuated PKD-stimulated cAMP and ERK\/Myc signaling pathways; reduced PKD-associated ciliary elongation, cell proliferation, and fibrosis; improved renal function; and prolonged survival. Importantly, senicapoc treatment of\n                    <jats:italic>Pkd1<\/jats:italic>\n                    mouse models phenocopied most effects of\n                    <jats:italic>Kcnn4<\/jats:italic>\n                    inactivation. This first study on the efficacy of KCa3.1 inhibition in PKD progression recommends senicapoc as a clinical trial candidate for ADPKD.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.191311","type":"journal-article","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T18:00:42Z","timestamp":1761069642000},"source":"Crossref","is-referenced-by-count":3,"title":["Kcnn4\/KCa3.1 inhibition blunts polycystic kidney disease progression in mouse models"],"prefix":"10.1172","volume":"10","author":[{"given":"Guanhan","family":"Yao","sequence":"first","affiliation":[{"name":"Molecular Genetics and Development, Institut de recherches cliniques de Montr\u00e9al, Montr\u00e9al, Qu\u00e9bec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Almira","family":"Kurbegovic","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Development, Institut de recherches cliniques de Montr\u00e9al, Montr\u00e9al, Qu\u00e9bec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camila","family":"Parrot","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Development, Institut de recherches cliniques de Montr\u00e9al, Montr\u00e9al, Qu\u00e9bec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Foley","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Development, Institut de recherches cliniques de Montr\u00e9al, Montr\u00e9al, Qu\u00e9bec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Roman","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Development, Institut de recherches cliniques de Montr\u00e9al, Montr\u00e9al, Qu\u00e9bec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seth L.","family":"Alper","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Vascular Biology Research Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA."},{"name":"Department of Medicine, Harvard Medical School, Massachusetts, USA."},{"name":"Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Trudel","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Development, Institut de recherches cliniques de Montr\u00e9al, Montr\u00e9al, Qu\u00e9bec, Canada."},{"name":"Department of Medicine, Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Qu\u00e9bec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2025,10,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1111\/j.0954-6820.1986.tb03276.x"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2012.139"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1998.78.4.1165"},{"issue":"4","key":"B4","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1093\/joneph\/19.4.529","article-title":"Autosomal dominant polycystic kidney disease coexisting with cystic fibrosis","volume":"19","author":"Xu","year":"2006","journal-title":"J Nephrol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2011.01.011"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2007070828"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.001846"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-18104-5"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2008.357"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-002-0880-3"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1993.265.5.C1271"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.1996.271.5.L775"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1172\/JCI117144"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.34.21542"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.21.11651"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M007716200"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.1.585"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1097\/HS9.0000000000000055"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcmd.2019.102346"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-02-482489"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-04-422253"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1172\/JCI116597"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1172\/JCI117149"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-08-110098"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M409627200"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000238377.08219.0c"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0910133107"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00104-12"},{"issue":"6","key":"B29","first-page":"1153","article-title":"Dysregulation of cellular proliferation and apoptosis mediates human autosomal dominant polycystic kidney disease (ADPKD)","volume":"13","author":"Lanoix","year":"1996","journal-title":"Oncogene"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/ki.1991.80"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddy379"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2008.246"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddn039"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0708217104"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00687-14"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddp588"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.26.4.1538-1548.2006"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.4.1524"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1023\/A:1026489723733"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1007\/BF03401654"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119090"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfy297"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.2215\/CJN.13661119"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2018.06.008"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/ki.1996.304"},{"key":"B46","article-title":"The role of Aquaporin-2 in cyst progression in autosomal dominant polycystic kidney disease","volume":"59","author":"Venkatesan","year":"2024","journal-title":"Proc Physiol Soc"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2006030295"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2010.08520.x"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.754"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.14.8151"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2013.418"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1021\/jm9009873"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1172\/JCI72272"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M405079200"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2009.11.072"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1186\/s40246-016-0095-x"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-22368-w"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2020101406"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1710964114"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2018.11.028"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-023-02978-x"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2018090912"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2014111067"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.329"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1242\/dev.149112"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2020.12.001"},{"issue":"1","key":"B67","first-page":"219","article-title":"Polycystic kidney disease in SBM transgenic mice: role of c-myc in disease induction and progression","volume":"152","author":"Trudel","year":"1998","journal-title":"Am J Pathol"},{"issue":"6","key":"B68","first-page":"1728","article-title":"Analysis of the role of membrane polarity in polycystic kidney disease of transgenic SBM mice","volume":"147","author":"Barisoni","year":"1995","journal-title":"Am J Pathol"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1159\/000421644"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-007-0521-4"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00153.2003"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1111\/j.1523-1755.2004.00843.x"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2005060645"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1008-14.2014"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1042\/AN20130031"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.2000.00991.x"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1016\/S0962-8924(02)02294-8"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-11-3605"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2211927120"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2020.109594"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2019103148"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1111\/apha.13447"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0903458106"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.2337\/db13-0135"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-015-1607-5"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v23.i23.4181"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2016-0092OC"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxlet.2018.07.020"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00352-06"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000086464.04719.DD"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.173.2.776"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00692.2011"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1172\/JCI64313"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pharmtox-010919-023420"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-58382-z"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.2c00567"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1038\/nm935"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2013121312"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.1995.268.3.F398"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.17345"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/11.16.1845"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1097\/01.ASN.0000144204.01352.86"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.1097\/01.ASN.0000016444.90348.50"},{"key":"B104","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2023.03.016"},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-17204-5"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/191311\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,17]],"date-time":"2026-05-17T15:01:12Z","timestamp":1779030072000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/191311"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,22]]},"references-count":105,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2025,10,22]]},"published-print":{"date-parts":[[2025,10,22]]}},"alternative-id":["10.1172\/jci.insight.191311"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.191311","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,22]]},"article-number":"e191311"}}