LAUSR

Kidneys have the capacity for intrinsic repair, preserving kidney architecture with return to a basal state after tubular injury. When injury is overwhelming or repetitive, however, that capacity is exceeded and incomplete repair results in fibrotic tissue replacing normal kidney parenchyma. Loss of nephrons correlates with reduced kidney function, which defines chronic kidney disease (CKD) and confers substantial morbidity and mortality to the worldwide population. Despite the identification of pathways involved in intrinsic repair, limited treatments for CKD exist, partly because of the limited throughput and predictivity of animal studies. Here, we showed that kidney organoids can model the transition from intrinsic to incomplete repair. Single-nuclear RNA sequencing of kidney organoids after cisplatin exposure identified 159 differentially expressed genes and 29 signal pathways in tubular cells undergoing intrinsic repair. Homology-directed repair (HDR) genes including Fanconi anemia complementation group D2 (FANCD2) and RAD51 recombinase (RAD51) were transiently up-regulated during intrinsic repair but were down-regulated in incomplete repair. Single cellular transcriptomics in mouse models of obstructive and hemodynamic kidney injury and human kidney samples of immune-mediated injury validated HDR gene up-regulation during tubular repair. Kidney biopsy samples with tubular injury and varying degrees of fibrosis confirmed loss of FANCD2 during incomplete repair. Last, we performed targeted drug screening that identified the DNA ligase IV inhibitor, SCR7, as a therapeutic candidate that rescued FANCD2/RAD51-mediated repair to prevent the progression of CKD in the cisplatin-induced organoid injury model. Our findings demonstrate the translational utility of kidney organoids to identify pathologic pathways and potential therapies. Description Disease modeling in kidney organoids identifies a conserved RAD51/FANCD2-mediated process that promotes effective repair. Fingering FANCD2 in tubular repair The transition from acute kidney injury, characterized by intrinsic repair, to incomplete repair and chronic damage has been difficult to study. Here, Gupta and colleagues modeled the transition from intrinsic to incomplete repair using human kidney organoids. A single exposure to cisplatin resulted in intrinsic repair, with preserved tubular architecture and up-regulation of genes associated with homology-directed repair, including Fanconi anemia complementation group D2 (FANCD2). However, with repeated cisplatin exposure, FANCD2 and RAD51 recombinase (RAD51) were down-regulated, leading to incomplete repair. The DNA ligase IV inhibitor SCR7 increased FANCD2-mediated repair and ameliorated progression to chronic injury in the organoids, suggesting that targeting the FANCD2/RAD51 pathway may have potential to treat kidney disease.