A FANCD2/FANCI-Associated Nuclease 1-Knockout Model Develops Karyomegalic Interstitial Nephritis
| العنوان: | A FANCD2/FANCI-Associated Nuclease 1-Knockout Model Develops Karyomegalic Interstitial Nephritis |
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| المؤلفون: | Sunder Sims-Lucas, Elina Mukherjee, Jang Cho, Friedhelm Hildebrandt, Merlin Airik, Rannar Airik, Markus Schueler, Jonathan D. Porath |
| المصدر: | Journal of the American Society of Nephrology. 27:3552-3559 |
| بيانات النشر: | Ovid Technologies (Wolters Kluwer Health), 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | 0301 basic medicine, Pathology, medicine.medical_specialty, DNA damage, Interstitial nephritis, Biology, medicine.disease_cause, Pathogenesis, Mice, 03 medical and health sciences, medicine, Animals, Renal Insufficiency, Chronic, Mice, Knockout, Kidney, Mutation, Endodeoxyribonucleases, FAN1, Bone marrow failure, General Medicine, medicine.disease, Multifunctional Enzymes, Disease Models, Animal, Exodeoxyribonucleases, 030104 developmental biology, medicine.anatomical_structure, Nephrology, Knockout mouse, Cancer research, Nephritis, Interstitial, Brief Communications |
| الوصف: | Karyomegalic interstitial nephritis (KIN) is a chronic interstitial nephropathy characterized by tubulointerstitial nephritis and formation of enlarged nuclei in the kidneys and other tissues. We recently reported that recessive mutations in the gene encoding FANCD2/FANCI-associated nuclease 1 (FAN1) cause KIN in humans. FAN1 is a major component of the Fanconi anemia–related pathway of DNA damage response (DDR) signaling. To study the pathogenesis of KIN, we generated a Fan1 knockout mouse model, with abrogation of Fan1 expression confirmed by quantitative RT-PCR. Challenging Fan1−/− and wild-type mice with 20 mg/kg cisplatin caused AKI in both genotypes. In contrast, chronic injection of cisplatin at 2 mg/kg induced KIN that led to renal failure within 5 weeks in Fan1−/− mice but not in wild-type mice. Cell culture studies showed decreased survival and reduced colony formation of Fan1−/− mouse embryonic fibroblasts and bone marrow mesenchymal stem cells compared with wild-type counterparts in response to treatment with genotoxic agents, suggesting that FAN1 mutations cause chemosensitivity and bone marrow failure. Our data show that Fan1 is involved in the physiologic response of kidney tubular cells to DNA damage, which contributes to the pathogenesis of CKD. Moreover, Fan1−/− mice provide a new model with which to study the pathomechanisms of CKD. |
| تدمد: | 1533-3450 1046-6673 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7af1d4795b4ecb22ac7d3d8665337f34Test https://doi.org/10.1681/asn.2015101108Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....7af1d4795b4ecb22ac7d3d8665337f34 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15333450 10466673 |
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