title: A FANCD2/FANCI-Associated Nuclease 1-Knockout Model Develops Karyomegalic Interstitial Nephritis.
abstract: 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.
authors.affiliation: Department of Medicine, Boston Children's Hospital, Boston, Massachusetts; airikr@pitt.edu Friedhelm.Hildebrandt@childrens.harvard.edu.
authors.forename: Rannar
authors.initials: R
authors.lastname: Airik
authors.affiliation: Department of Medicine, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Markus
authors.initials: M
authors.lastname: Schueler
authors.affiliation: Department of Medicine, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Merlin
authors.initials: M
authors.lastname: Airik
authors.affiliation: Department of Medicine, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Jang
authors.initials: J
authors.lastname: Cho
authors.affiliation: Department of Medicine, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Porath
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; and.
authors.forename: Elina
authors.initials: E
authors.lastname: Mukherjee
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; and.
authors.forename: Sunder
authors.initials: S
authors.lastname: Sims-Lucas
authors.affiliation: Department of Medicine, Boston Children's Hospital, Boston, Massachusetts; airikr@pitt.edu Friedhelm.Hildebrandt@childrens.harvard.edu.|Howard Hughes Medical Institute, Chevy Chase, Maryland.
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004706:Endodeoxyribonucleases / Q000235:genetics*; D005090:Exodeoxyribonucleases; D051379:Mice; D018345:Mice, Knockout; D064251:Multifunctional Enzymes; D009154:Mutation; D009395:Nephritis, Interstitial / Q000201:enzymology* / Q000235:genetics*; D051436:Renal Insufficiency, Chronic / Q000209:etiology
chemical_list: D064251:Multifunctional Enzymes; D004706:Endodeoxyribonucleases; D005090:Exodeoxyribonucleases; C000596972:Fan1 protein, mouse
keywords: DNA damage response signaling; FAN1; chronic kidney disease; genetic renal disease; karyomegalic interstitial nephritis