title: Loss of Glis2/NPHP7 causes kidney epithelial cell senescence and suppresses cyst growth in the Kif3a mouse model of cystic kidney disease.
abstract: Enlargement of kidney tubules is a common feature of multiple cystic kidney diseases in humans and mice. However, while some of these pathologies are characterized by cyst expansion and organ enlargement, in others, progressive interstitial fibrosis and kidney atrophy prevail. The Kif3a knockout mouse is an established non-orthologous mouse model of cystic kidney disease. Conditional inactivation of Kif3a in kidney tubular cells results in loss of primary cilia and rapid cyst growth. Conversely, loss of function of the gene GLIS2/NPHP7 causes progressive kidney atrophy, interstitial inflammatory infiltration, and fibrosis. Kif3a null tubular cells have unrestrained proliferation and reduced stabilization of p53 resulting in a loss of cell cycle arrest in the presence of DNA damage. In contrast, loss of Glis2 is associated with activation of checkpoint kinase 1, stabilization of p53, and induction of cell senescence. Interestingly, the cystic phenotype of Kif3a knockout mice is partially rescued by genetic ablation of Glis2 and pharmacological stabilization of p53. Thus, Kif3a is required for cell cycle regulation and the DNA damage response, whereas cell senescence is significantly enhanced in Glis2 null cells. Hence, cell senescence is a central feature in nephronophthisis type 7 and Kif3a is unexpectedly required for efficient DNA damage response and cell cycle arrest.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Lu
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Alysha
authors.initials: A
authors.lastname: Rauhauser
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Binghua
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Chongyu
authors.initials: C
authors.lastname: Ren
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Kayla
authors.initials: K
authors.lastname: McEnery
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Nephrology, Renmin Hospital, Wuhan University, Wuhan, Hubei, China.
authors.forename: Jili
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Moumita
authors.initials: M
authors.lastname: Chaki
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Komal
authors.initials: K
authors.lastname: Vadnagara
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Elhadi
authors.affiliation: Cell Biology Section, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
authors.forename: Anton M
authors.initials: AM
authors.lastname: Jetten
authors.affiliation: Department of Internal Medicine, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Igarashi
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; Eugene McDermott Center for Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: massimo.attanasio@utsouthwestern.edu.
authors.forename: Massimo
authors.initials: M
authors.lastname: Attanasio
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics*; D000071877:Checkpoint Kinase 1 / Q000378:metabolism; D002923:Cilia / Q000473:pathology; D003560:Cysts / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D005355:Fibrosis; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D052177:Kidney Diseases, Cystic / Q000235:genetics*; D007684:Kidney Tubules / Q000166:cytology / Q000502:physiology*; D016547:Kinesins / Q000235:genetics*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D010641:Phenotype; D010879:Piperazines / Q000494:pharmacology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C430270:Gli5 protein, mouse; D007093:Imidazoles; C490202:Kif3a protein, mouse; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D010879:Piperazines; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; D016547:Kinesins
keywords: DNA damage; Kif3a; cystic kidney disease; nephronophthisis; senescence