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Abstract: FR-PO620

Mitochondrial Reactive Oxygen Species (ROS) Triggers Karyomegalic Interstitial Nephritis (KIN) Pathogenesis in FAN1-Deficient Kidneys

Session Information

Category: Genetic Diseases of the Kidneys

  • 1202 Genetic Diseases of the Kidneys: Non-Cystic


  • Airik, Merlin, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, United States
  • Goetzman, Eric S., Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, United States
  • Kmoch, Stanislav, Univerzita Karlova, Praha, Czechia
  • Conlon, Peter J., Beaumont Hospital, Dublin, Ireland
  • Bleyer, Anthony J., Wake Forest Baptist Medical Center, Winston-Salem, North Carolina, United States
  • Airik, Rannar, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, United States

Karyomegalic interstitial nephritis (KIN) is a genetic adult-onset chronic kidney disease (CKD) characterized by genomic instability and mitotic abnormalities in the tubular epithelial cells. KIN is caused by recessive mutations in the FAN1 DNA repair enzyme. However, the endogenous source of DNA damage in FAN1/KIN kidneys has not been identified.


KIN was induced in 12-week-old Fan1 KO mice by employing low dose cisplatin injury models: one mimicking AKI (1 x 2 mg/kg cisplatin), and another CKD (weekly 5 x 2 mg/kg cisplatin). Coincident with cisplatin, mice were administered a novel mitochondrial ROS and electron scavenger JP4-039 at a dose of 10 mg/kg. Histological analysis was performed using PAS and HE. Markers of tubular injury, DNA damage and fibrosis were assessed by IF and IHC. Human kidney proximal tubular cells (PTECs) were used to model FAN1 loss of function in vitro. RNA-seq analysis was performed to identify transcriptional changes in KIN. Mitochondrial OXPHOS was measured using the Oroboros Oxygraph-2k System. Metabolite measurements were preformed using YSI 7100 Bioanalyzer.


Transcriptional profiling of kidneys with KIN revealed a significant downregulation of genes involved in mitochondrial energy metabolism - OXPHOS, fatty acid oxidation (FAO) and peroxisomal function. Metabolic analysis of FAN1KO PTECs showed a defect in respiratory chain, increased oxidative stress and a shift to increased lactate secretion. Similarly, Fan1 KO kidneys revealed marked increase in oxidative DNA damage (8-OHdG), lipid peroxidation (4-HNE) and tubular lipotoxicity (OilRedO) after AKI or CKD. Treatment with mitochondrial ROS scavenger reduced the level of oxidative lesions in Fan1 KO kidneys, mitigated tubular damage and blocked the formation of KIN.


Loss of FAN1 causes defective mitochondrial metabolism and increased ROS generation in the kidney which give rise to oxidative DNA lesions and results in KIN. Blocking mitochondrial ROS protects Fan1 KO kidneys from DNA damage accumulation, mitigates tubular injury and improves kidney function in mice.


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