A new study conducted on human kidney organoids has identified a compound that may prevent permanent kidney damage and could halt the progression of chronic kidney disease (CKD).
Researchers at Massachusetts General Hospital used kidney organoids grown from human stem cells to identify genes that play an important role in the repair of tissue damage. Kidneys have the capability to repair damage and preserve kidney architecture following tubular injury. However, if major damage is suffered or when there is repetitive damage, the capacity for repair is exceeded. That results in incomplete repair and fibrotic tissue replaces normal kidney parenchyma, resulting in the permanent loss of kidney function. The loss of nephrons is what defined CKD.
Previous studies conducted on animals have identified some of the pathways involved in intrinsic kidney repair, and while treatments have been developed that have proved promising in animal studies, the results have not been replicated in clinical trials. Treatments have either proven to be ineffective in humans or were found to be toxic.
The researchers explored the genes involved in kidney repair by exposing the human kidney organoids to the chemotherapy drug cisplatin. The researchers identified 159 genes and 29 signal pathways in kidney cells that were undergoing intrinsic repair. The researchers then identified two genes – FANCD2 and Rad51 – that were activated during the intrinsic repair process, but once the damage became irreversible, expression was reduced. These genes are associated with the repair of DNA when it is damaged inside cells.
In follow on studies in a mouse model of kidney injuries, the researchers confirmed the findings. They also found from kidney biopsies with tubular injury and different levels of fibrosis that there was a loss of FANCD2 during incomplete repair. The researchers identified a compound called SCR7, which is a DNA ligase IV inhibitor, that was found to maintain FANCD2 and RAD51 activity, which they demonstrated could rescue the normal repair process and prevent the progression of CKD in their kidney organoids after treatment with cisplatin.
“We have shown that the activation of a DNA repair mechanism can help to maintain healthy kidney status,” said senior author, Ryuji Morizane, MD, Ph.D., a principal investigator in the Division of Nephrology at MGH. “In the future, this approach might become a new therapeutic option for patients with CKD.”
You can read more about the study in the paper – Modeling injury and repair in kidney organoids reveals that homologous recombination governs tubular intrinsic repair – which was recently published in Science Translational Medicine. DOI: