Kidney organoids used to reveal genes involved in preventing irreversible kidney damage
A team of researchers from Massachusetts General Hospital (MGH; MA, USA) have discovered a compound in kidney organoids that can support DNA repair, preventing irreversible damage and chronic kidney disease development. During the study they utilized kidney organoids derived from human stem cells to identify the genes involved with maintaining healthy levels of repair in the kidneys.
The team believe that their findings will aid in the prevention or treatment of chronic kidney disease (CKD) in the future. Kidneys have some capacity to regenerate themselves after injury, but a change can happen from intrinsic repair to incomplete repair that results in irreversible damage and CKD.
There are a range of factors involved with kidney repair that have previously been identified in animal studies. Researchers suggested that translating this to the clinic is not straightforward because many treatments that are effective in animals that have been deemed unsafe for humans. Therefore, the research team decided to use kidney organoids in order to investigate and identify human-safe treatment.
Navin Gupta, Investigator within the Division of Nephrology at MGH and lead author of the study stated: “we have pioneered the work of human kidney organoids and think they’ll be useful for therapeutic development for CKD, as physician-scientists, we wanted to create a new CKD model in human cells to facilitate drug development.”
Throughout the study, the research team exposed human kidney organoids to the drug cisplatin – a chemotherapy drug, which can be harmful to the kidneys. They discovered that treatment altered the express of 159 genes and 29 signal pathways within kidney cells undergoing intrinsic repair.
Many of the genes they previously identified, including FANCD2 and RAD51, were activated during intrinsic repair but their expression decreased as kidney damage became irreparable. These genes are responsible for coding for proteins that are involved in the repair of DNA when it becomes damaged.
In addition, the researchers conducted studies in mouse models of kidney injury and human kidney biopsies, which confirmed their findings found in kidney organoids. Through drug screenings, the researcher team discovered a compound known as SCR7 that assisted in the maintenance of FANCD2 and RAD51 activity to prevent the progression of CKD.
Ryuji Morizane, principal investigator in the Division of Nephrology at MGH and co-author of the study, stated: “we have shown that the activation of a DNA repair mechanism can help to maintain healthy kidney status, in the future, this approach might become a new therapeutic option for patients with CKD.”
With further research, this discovery could lead to new therapeutic targets for kidney regeneration and potential treatments for CKD in the clinical setting.
Source: Gupta N, Matsumoto T, Saiz E et al. Modeling injury and repair in kidney organoids reveals that homologous recombination governs tubular intrinsic repair. Sci Transl Med. 14(634) (2022).