ArticleKidney international2022
Persistent DNA damage underlies tubular cell polyploidization and progression to chronic kidney disease in kidneys deficient in the DNA repair protein FAN1.
Article in Kidney international, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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21 citing papers in PubMed, 35 citations in OpenAlex.
- TRIM21 inhibition alleviates acute kidney injury by promoting INTS3-associated DNA damage repair.Apoptosis : an international journal on programmed cell death · 2026Article
- Dysregulation of the DNA repair‑immune axis: Targeted therapeutic strategies for autoimmune diseases (Review).International journal of molecular medicine · 2026Review
- Transition from acute kidney injury to chronic kidney disease: molecular mechanisms and therapeutic interventions.Molecular biomedicine · 2026Review
- Decoding organ fibrosis: mechanistic insights and emerging therapeutic strategies.Signal transduction and targeted therapy · 2026Review
- Distinct p21 dynamics drive alternative routes to whole-genome duplication through a common CDK4/6-dependent polyploid G0 state.bioRxiv : the preprint server for biology · 2026Article
- CRESTA: a comprehensive transcriptome atlas for cellular response to external stressors.Nucleic acids research · 2026Article
- Life history enlightened therapies: cell cycle mapping to identify molecular targets to prevent hepatocellular carcinoma.Evolution, medicine, and public health · 2026Article
- Comprehensive review on Fanconi anemia: insights into DNA interstrand cross-links, repair pathways, and associated tumors.Orphanet journal of rare diseases · 2025Review
- Tubular Cell Polyploidy and AKI-to-CKD Transition.Journal of the American Society of Nephrology : JASN · 2025Article
- Fanconi syndrome with karyomegalic interstitial nephritis after ifosfamide treatment for osteosarcoma: a case report.CEN case reports · 2025Article
- The unexpected diagnosis of karyomegalic interstitial nephritis in a presumed case of Mesoamerican Nephropathy: a case report.Frontiers in medicine · 2025Article
- Article
- Phenotypic and Genotypic Features of theInternational journal of molecular sciences · 2024Article
- Minichromosome maintenance 6 protects against renal fibrogenesis by regulating DUSP6-mediated ERK/GSK-3β/Snail1 signaling.iScience · 2023Article
- Chronic kidney disease in children: an update.Clinical kidney journal · 2023Review
- Polyploid tubular cells initiate a TGF-β1 controlled loop that sustains polyploidization and fibrosis after acute kidney injury.American journal of physiology. Cell physiology · 2023Article
- Modeling ofCells · 2023Article
- Karyomegalic interstitial nephritis as a rare cause of kidney graft dysfunction: case report and review of literature.BMC nephrology · 2023Review
- Mitochondrial ROS Triggers KIN Pathogenesis in FAN1-Deficient Kidneys.Antioxidants (Basel, Switzerland) · 2023Article
- Tubular-specific expression of HIV protein Vpr leads to severe tubulointerstitial damage accompanied by progressive fibrosis and cystic development.Kidney international · 2023Article
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11 authors at 5 institutions in 2 countries.
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Abstract
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.
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