Persistent DNA damage underlies tubular cell polyploidization and progression to chronic kidney disease in kidneys deficient in the DNA repair protein FAN1.
DNA damage
DNA re-replication
FAN1
chronic kidney disease
karyomegalic interstitial nephritis
Journal
Kidney international
ISSN: 1523-1755
Titre abrégé: Kidney Int
Pays: United States
ID NLM: 0323470
Informations de publication
Date de publication:
11 2022
11 2022
Historique:
received:
11
10
2021
revised:
24
06
2022
accepted:
06
07
2022
pubmed:
6
8
2022
medline:
26
10
2022
entrez:
5
8
2022
Statut:
ppublish
Résumé
Defective DNA repair pathways contribute to the development of chronic kidney disease (CKD) in humans. However, the molecular mechanisms underlying DNA damage-induced CKD pathogenesis are not well understood. Here, we investigated the role of tubular cell DNA damage in the pathogenesis of CKD using mice in which the DNA repair protein Fan1 was knocked out. The phenotype of these mice is orthologous to the human DNA damage syndrome, karyomegalic interstitial nephritis (KIN). Inactivation of Fan1 in kidney proximal tubule cells sensitized the kidneys to genotoxic and obstructive injury characterized by replication stress and persistent DNA damage response activity. Accumulation of DNA damage in Fan1 tubular cells induced epithelial dedifferentiation and tubular injury. Characteristic to KIN, cells with chronic DNA damage failed to complete mitosis and underwent polyploidization. In vitro and in vivo studies showed that polyploidization was caused by the overexpression of DNA replication factors CDT1 and CDC6 in FAN1 deficient cells. Mechanistically, inhibiting DNA replication with Roscovitine reduced tubular injury, blocked the development of KIN and mitigated kidney function in these Fan1 knockout mice. Thus, our data delineate a mechanistic pathway by which persistent DNA damage in the kidney tubular cells leads to kidney injury and development of CKD. Furthermore, therapeutic modulation of cell cycle activity may provide an opportunity to mitigate the DNA damage response induced CKD progression.
Identifiants
pubmed: 35931300
pii: S0085-2538(22)00545-2
doi: 10.1016/j.kint.2022.07.003
pmc: PMC9588672
mid: NIHMS1827849
pii:
doi:
Substances chimiques
Endodeoxyribonucleases
EC 3.1.-
Exodeoxyribonucleases
EC 3.1.-
FAN1 protein, human
EC 3.1.-
Fan1 protein, mouse
EC 3.1.-
Multifunctional Enzymes
0
Roscovitine
0ES1C2KQ94
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
1042-1056Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK115403
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
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