{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T00:41:23Z","timestamp":1792802483009,"version":"4.5.0"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK100592"],"award-info":[{"award-number":["DK100592"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK120911"],"award-info":[{"award-number":["DK120911"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"name":"FAPESP State of Sao Paolo Research Foundation","id":[{"id":"https:\/\/ror.org\/02ddkpn78","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/100001296","name":"PKD Foundation","doi-asserted-by":"publisher","award":["211f18a"],"award-info":[{"award-number":["211f18a"]}],"id":[{"id":"10.13039\/100001296","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["JASN"],"published-print":{"date-parts":[[2021,1]]},"abstract":"\n Significance Statement<\/jats:title>\n \n Aberrantly upregulated cell proliferation in kidney tubule cyst cells promotes cyst progression in autosomal dominant polycystic kidney disease (ADPKD), but how mutations in polycystin genes increase cell proliferation is poorly understood. Unbiased transcriptional profiling in mouse models identified early changes in gene expression following inactivation of polycystins. Cell proliferation was the most upregulated pathway, with cyclin-dependent kinase 1 (\n Cdk1<\/jats:italic>\n ) a central component. Mouse models with inactivated polycystic kidney disease 1 (\n Pkd1<\/jats:italic>\n ) alone or with\n Cdk1<\/jats:italic>\n revealed that loss of\n Cdk1<\/jats:italic>\n significantly slowed kidney cyst growth by blocking the increased cell proliferation that follows inactivation of\n Pkd1<\/jats:italic>\n .\n Cdk1<\/jats:italic>\n , therefore, is a critical driver of cyst cell proliferation, and targeting it effectively inhibits cyst growth in ADPKD.\n <\/jats:p>\n <\/jats:sec>\n \n Background<\/jats:title>\n \n Mutations in\n PKD1<\/jats:italic>\n and\n PKD2<\/jats:italic>\n , which encode the transmembrane proteins polycystin-1 and polycystin-2, respectively, cause autosomal dominant polycystic kidney disease (ADPKD). Polycystins are expressed in the primary cilium, and disrupting cilia structure significantly slows ADPKD progression following inactivation of polycystins. The cellular mechanisms of polycystin- and cilia-dependent cyst progression in ADPKD remain incompletely understood.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Unbiased transcriptional profiling in an adult-onset\n Pkd2<\/jats:italic>\n mouse model before cysts formed revealed significant differentially expressed genes (DEGs) in\n Pkd2<\/jats:italic>\n single-knockout kidneys, which were used to identify candidate pathways dysregulated in kidneys destined to form cysts.\n In vivo<\/jats:italic>\n studies validated the role of the candidate pathway in the progression of ADPKD. Wild-type and\n Pkd2\/Ift88<\/jats:italic>\n double-knockout mice that are protected from cyst growth served as controls.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n The RNASeq data identified cell proliferation as the most dysregulated pathway, with 15 of 241 DEGs related to cell cycle functions.\n Cdk1<\/jats:italic>\n appeared as a central component in this analysis.\n Cdk1<\/jats:italic>\n expression was similarly dysregulated in\n Pkd1<\/jats:italic>\n models of ADPKD, and conditional inactivation of\n Cdk1<\/jats:italic>\n with\n Pkd1<\/jats:italic>\n markedly improved the cystic phenotype and kidney function compared with inactivation of\n Pkd1<\/jats:italic>\n alone. The\n Pkd1<\/jats:italic>\n \/\n Cdk1<\/jats:italic>\n double knockout blocked cyst cell proliferation that otherwise accompanied\n Pkd1<\/jats:italic>\n inactivation alone.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Dysregulation of\n Cdk1<\/jats:italic>\n is an early driver of cyst cell proliferation in ADPKD due to\n Pkd1<\/jats:italic>\n inactivation. Selective targeting of cyst cell proliferation is an effective means of slowing ADPKD progression caused by inactivation of\n Pkd1<\/jats:italic>\n .\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1681\/asn.2020040511","type":"journal-article","created":{"date-parts":[[2020,10,12]],"date-time":"2020-10-12T20:35:24Z","timestamp":1602534924000},"page":"41-51","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":47,"title":["Cyclin-Dependent Kinase 1 Activity Is a Driver of Cyst Growth in Polycystic Kidney Disease"],"prefix":"10.1681","volume":"32","author":[{"given":"Chao","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Yale University, New Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Balbo","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Yale University, New Haven, 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