While the human kidney has an innate ability to repair itself from disease-related damage, it also has a point of no return, when damage becomes irreparable and risks organ failure. In a new Science Translational Medicine study, Navin Gupta, an organoid researcher at Massachusetts General Hospital, and his team used kidney organoids to identify a mechanism of DNA damage control that may lead to this permanent injury, as well as a drug that could reverse the damage.
“[The study] is novel, and it has a very good message to the field to provide kidney organoids as a model for [acute kidney injury],” said Zhongwei Li, a kidney disease researcher at the University of Southern California who was not involved in the study.
Organoids are small, human stem-cell derived tissue cultures with features similar to human organs. Although they do not represent the full architecture of a mature organ, they help researchers glean insight into disease mechanisms. Organoid studies are also less expensive than traditional drug studies performed in mice.
Gupta emphasized the potential of organoids to bridge the gap between basic research and clinical studies, particularly for diseases known as ‘orphans,’ which are so rare that resources are rarely directed toward studying them. “There are a lot of human diseases that have very poor animal models or no animal model at all, in which case…there's a perfect niche for organoids to be the only sort of preclinical model for clinical trials.”
In this newly published study, Gupta’s team investigated the mechanisms of kidney repair after injury by repeatedly exposing kidney organoids to a chemical toxin. During the first several injuries, they monitored changes in the organoids’ tubular cells, which are particularly vulnerable to injury and mediate fibrosis of the kidney. The DNA of these tubular cells underwent homology-directed repair, a method of fixing double-stranded DNA breaks. This DNA repair mechanism enabled cells to reverse the damage done to the kidney organoids.
However, after several repeated injuries, the kidney organoids suffered irreversible DNA damage and tubular atrophy, a characteristic symptom of chronic kidney disease. At the same time, the expression of an important homology-directed repair gene, FANCD2, plummeted. To Gupta and his team, these observations suggested that homology-directed repair is crucial to kidney recovery from acute injury, and without it, the kidney can no longer repair itself.
To investigate whether or not this mechanism is also important in human kidneys, Gupta and his team compared the transcriptomes of their kidney organoids with data from rodent models of kidney injury and transplanted kidneys rejected by their human recipients’ immune systems. The researchers found that in all cases, worsening kidney fibrosis corresponded with reduced DNA repair gene expression.
Gupta emphasized that this transcriptomic dataset would be useful beyond validating the findings of this study. “We also wanted to create a rich dataset that could be mined in the future for things that we hadn't seen,” he said.
Since DNA repair machinery appeared to be the culprit for permanent kidney damage, the researchers performed a drug screen for small molecules that could rescue this repair defect. They identified a DNA ligase inhibitor called SCR7 that increased DNA repair gene expression during kidney injury, and tubular structure markers indicated that with SCR7 treatment, tubular atrophy did not worsen after injury in the organoid models either. To Gupta’s team, these findings suggested that reversing this newly discovered disease pathway could lead to improved outcomes for kidney disease patients.
Gupta was excited about the potential for these results to improve the ease of drug discovery within the field. “We've created a model of the transition from acute kidney injury to chronic kidney disease in kidney organoids that doesn't require any specialized techniques or equipment beyond the ability to generate kidney organoids,” he said. “Multiple labs can use this as a screening tool to identify new drug targets and evaluate lead candidates during drug development.”
Now that Gupta and his team have identified this drug candidate using their organoid model, they plan to further evaluate the specifics of the mechanism they identified.
“The rational next step for the study is to evaluate whether the small molecule they identified or the disease mechanism they identified could be employed to develop novel therapies, more clinical models, preclinical models, and to see if eventually it can develop into a new therapy to help the patients,” Li said.
Gupta, N. et al. Modeling injury and repair in kidney organoids reveals that homologous recombination governs tubular intrinsic repair. Sci Transl Med 14, ej4772 (2022).