Modeling injury and repair in kidney organoids reveals that homologous recombination governs tubular intrinsic repair

Author:

Gupta Navin1234ORCID,Matsumoto Takuya124,Hiratsuka Ken1245ORCID,Garcia Saiz Edgar24ORCID,Zhang Chengcheng1,Galichon Pierre346ORCID,Miyoshi Tomoya4ORCID,Susa Koichiro4ORCID,Tatsumoto Narihito7,Yamashita Michifumi7ORCID,Morizane Ryuji12345ORCID

Affiliation:

1. Nephrology Division, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.

2. Harvard Medical School, Boston, MA 02115, USA.

3. Harvard Stem Cell Institute (HSCI), Cambridge, MA 02138, USA.

4. Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA.

5. Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.

6. Sorbonne Université, INSERM UMR-S1155, Paris, France.

7. Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

General Medicine

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