Cyclin-Dependent Kinase 1 Activity Is a Driver of Cyst Growth in Polycystic Kidney Disease.

Abstract

Mutations in <i>PKD1</i> and <i>PKD2</i>, 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. Unbiased transcriptional profiling in an adult-onset <i>Pkd2</i> mouse model before cysts formed revealed significant differentially expressed genes (DEGs) in <i>Pkd2</i> single-knockout kidneys, which were used to identify candidate pathways dysregulated in kidneys destined to form cysts. <i>In vivo</i> studies validated the role of the candidate pathway in the progression of ADPKD. Wild-type and <i>Pkd2/Ift88</i> double-knockout mice that are protected from cyst growth served as controls. The RNASeq data identified cell proliferation as the most dysregulated pathway, with 15 of 241 DEGs related to cell cycle functions. <i>Cdk1</i> appeared as a central component in this analysis. <i>Cdk1</i> expression was similarly dysregulated in <i>Pkd1</i> models of ADPKD, and conditional inactivation of <i>Cdk1</i> with <i>Pkd1</i> markedly improved the cystic phenotype and kidney function compared with inactivation of <i>Pkd1</i> alone. The <i>Pkd1</i>/<i>Cdk1</i> double knockout blocked cyst cell proliferation that otherwise accompanied <i>Pkd1</i> inactivation alone. Dysregulation of <i>Cdk1</i> is an early driver of cyst cell proliferation in ADPKD due to <i>Pkd1</i> inactivation. Selective targeting of cyst cell proliferation is an effective means of slowing ADPKD progression caused by inactivation of <i>Pkd1</i>.