Persistent DNA damage underlies tubular cell polyploidization and progression to chronic kidney disease in kidneys deficient in the DNA repair protein FAN1

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. 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. Polyploid tubular cells and chronic kidney diseaseKidney InternationalVol. 102Issue 5PreviewDefective DNA repair drives chronic kidney disease (CKD), but mechanisms are unclear. Airik and colleagues use a genetic model of defective DNA repair mimicking karyomegalic nephritis, a form of CKD characterized by tubular epithelial cells (TEC) with large nuclei and tubulointerstitial nephritis. They show that DNA damage in TEC triggers endoreplication leading to polyploid TEC and CKD. Blocking endoreplication preserved kidney function, suggesting that DNA damage triggers CKD via TEC polyploidization, questioning the concept of G2/M-arrest. Full-Text PDF