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

Chao Zhang, Bruno Balbo, Ming Ma, Jun Zhao, Xin Tian, Yuval Kluger and Stefan Somlo
JASN January 2021, 32 (1) 41-51; DOI: https://doi.org/10.1681/ASN.2020040511
Chao Zhang
1Department of Internal Medicine, Yale University, New Haven, Connecticut
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Bruno Balbo
1Department of Internal Medicine, Yale University, New Haven, Connecticut
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Ming Ma
1Department of Internal Medicine, Yale University, New Haven, Connecticut
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Jun Zhao
2Department of Pathology, Yale University, New Haven, Connecticut
3Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut
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Xin Tian
1Department of Internal Medicine, Yale University, New Haven, Connecticut
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Yuval Kluger
2Department of Pathology, Yale University, New Haven, Connecticut
3Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut
4Program in Applied Mathematics, Yale University, New Haven, Connecticut
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Stefan Somlo
1Department of Internal Medicine, Yale University, New Haven, Connecticut
5Department of Genetics, Yale University, New Haven, Connecticut
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Significance Statement

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 (Cdk1) a central component. Mouse models with inactivated polycystic kidney disease 1 (Pkd1) alone or with Cdk1 revealed that loss of Cdk1 significantly slowed kidney cyst growth by blocking the increased cell proliferation that follows inactivation of Pkd1. Cdk1, therefore, is a critical driver of cyst cell proliferation, and targeting it effectively inhibits cyst growth in ADPKD.

Abstract

Background Mutations in PKD1 and PKD2, 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.

Methods Unbiased transcriptional profiling in an adult-onset Pkd2 mouse model before cysts formed revealed significant differentially expressed genes (DEGs) in Pkd2 single-knockout kidneys, which were used to identify candidate pathways dysregulated in kidneys destined to form cysts. In vivo studies validated the role of the candidate pathway in the progression of ADPKD. Wild-type and Pkd2/Ift88 double-knockout mice that are protected from cyst growth served as controls.

Results The RNASeq data identified cell proliferation as the most dysregulated pathway, with 15 of 241 DEGs related to cell cycle functions. Cdk1 appeared as a central component in this analysis. Cdk1 expression was similarly dysregulated in Pkd1 models of ADPKD, and conditional inactivation of Cdk1 with Pkd1 markedly improved the cystic phenotype and kidney function compared with inactivation of Pkd1 alone. The Pkd1/Cdk1 double knockout blocked cyst cell proliferation that otherwise accompanied Pkd1 inactivation alone.

Conclusions Dysregulation of Cdk1 is an early driver of cyst cell proliferation in ADPKD due to Pkd1 inactivation. Selective targeting of cyst cell proliferation is an effective means of slowing ADPKD progression caused by inactivation of Pkd1.

  • ADPKD
  • proliferation
  • transcriptional profiling
  • Copyright © 2021 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 32 (1)
Journal of the American Society of Nephrology
Vol. 32, Issue 1
January 2021
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Cyclin-Dependent Kinase 1 Activity Is a Driver of Cyst Growth in Polycystic Kidney Disease
Chao Zhang, Bruno Balbo, Ming Ma, Jun Zhao, Xin Tian, Yuval Kluger, Stefan Somlo
JASN Jan 2021, 32 (1) 41-51; DOI: 10.1681/ASN.2020040511

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Cyclin-Dependent Kinase 1 Activity Is a Driver of Cyst Growth in Polycystic Kidney Disease
Chao Zhang, Bruno Balbo, Ming Ma, Jun Zhao, Xin Tian, Yuval Kluger, Stefan Somlo
JASN Jan 2021, 32 (1) 41-51; DOI: 10.1681/ASN.2020040511
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