Roscovitine blocks collecting duct cyst growth in Cep164-deficient kidneys.
Animals
Animals, Newborn
Cell Cycle
/ drug effects
Cilia
/ pathology
Ciliopathies
/ drug therapy
Cyclin-Dependent Kinases
/ antagonists & inhibitors
Disease Models, Animal
Drug Evaluation, Preclinical
Embryo, Mammalian
Epithelium
/ drug effects
Female
Humans
Kidney Diseases, Cystic
/ drug therapy
Kidney Tubules, Collecting
/ cytology
Male
Mice
Mice, Knockout
Microtubule Proteins
/ deficiency
Organoselenium Compounds
Proof of Concept Study
Protein Kinase Inhibitors
/ administration & dosage
Roscovitine
/ administration & dosage
CEP164
centrosome
cilia
nephronophthisis
polycystic kidney disease
Journal
Kidney international
ISSN: 1523-1755
Titre abrégé: Kidney Int
Pays: United States
ID NLM: 0323470
Informations de publication
Date de publication:
08 2019
08 2019
Historique:
received:
13
12
2018
revised:
11
03
2019
accepted:
05
04
2019
pubmed:
30
6
2019
medline:
2
10
2020
entrez:
29
6
2019
Statut:
ppublish
Résumé
Nephronophthisis is an autosomal recessive kidney disease with high genetic heterogeneity. Understanding the functions of the individual genes contributing to this disease is critical for delineating the pathomechanisms of this disorder. Here, we investigated kidney function of a novel gene associated with nephronophthisis, CEP164, coding a centriolar distal appendage protein, using a Cep164 knockout mouse model. Collecting duct-specific deletion of Cep164 abolished primary cilia from the collecting duct epithelium and led to rapid postnatal cyst growth in the kidneys. Cell cycle and biochemical studies revealed that tubular hyperproliferation is the primary mechanism that drives cystogenesis in the kidneys of these mice. Administration of roscovitine, a cell cycle inhibitor, blocked cyst growth in the cortical collecting ducts and preserved kidney parenchyma in Cep164 knockout mice. Thus, our findings provide evidence that therapeutic modulation of cell cycle activity can be an effective approach to prevent cyst progression in the kidney.
Identifiants
pubmed: 31248650
pii: S0085-2538(19)30472-7
doi: 10.1016/j.kint.2019.04.014
pmc: PMC6650321
mid: NIHMS1528880
pii:
doi:
Substances chimiques
Cep164 protein, mouse
0
Microtubule Proteins
0
Organoselenium Compounds
0
Protein Kinase Inhibitors
0
diselanylbis(1,3-dimethyl-1H-imidazol-3-ium)
0
Roscovitine
0ES1C2KQ94
Cyclin-Dependent Kinases
EC 2.7.11.22
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
320-326Subventions
Organisme : NIDDK NIH HHS
ID : P30 DK079307
Pays : United States
Organisme : NIDDK NIH HHS
ID : K99 DK099434
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK068306
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK115403
Pays : United States
Organisme : NIDDK NIH HHS
ID : R00 DK099434
Pays : United States
Informations de copyright
Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
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