Modeling injury and repair in kidney organoids reveals that homologous
recombination governs tubular intrinsic repair.
Authors Gupta N, Matsumoto T, Hiratsuka K, Garcia Saiz E, Galichon P, Miyoshi T, Susa K,
Tatsumoto N, Yamashita M, Morizane R
Submitted By Submitted Externally on 3/22/2022
Status Published
Journal Science translational medicine
Year 2022
Date Published 3/1/2022
Volume : Pages 14 : eabj4772
PubMed Reference 35235339
Abstract 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.