Activating a DNA repair mechanism may help preserve kidney function in people with chronic kidney disease

A compound called SCR7 supports DNA repair to prevent irreparable tissue damage and the progression of chronic kidney disease. To some degree, the kidneys have the ability to repair themselves after being injured, but a shift from such intrinsic repair to incomplete repair that leads to irreversible damage and chronic kidney disease (CKD) can occur. A team led by researchers at Massachusetts General Hospital (MGH) recently used kidney organoids derived from human stem cells to identify genes that are important for maintaining healthy kidney repair. The conclusions, which are published in Science Translational Medicinemay lead to new targets to help prevent or treat CKD.

Although various factors involved in kidney repair have been identified in animal studies, translating these findings into the clinic has been difficult because many treatments found to be safe and effective in animals have subsequently been found to be toxic or ineffective in trials. clinics. Human kidney organoids, which look like miniature kidneys, may help researchers avoid these setbacks.

“We pioneered work on human kidney organoids and believe they will be useful for therapeutic development in CKD,” says lead author Navin Gupta, MD, researcher in the MGH’s Division of Nephrology. . “As physician-scientists, we wanted to create a new CKD model in human cells to aid in drug development.”

When Gupta and his colleagues exposed human kidney organoids to cisplatin, a chemotherapeutic drug, which can damage the kidneys, the treatment altered the expression of 159 genes and 29 signaling pathways in kidney cells undergoing intrinsic repair. Many of the genes they identified, including 2 called FANCD2 and Rad51, were activated during intrinsic repair, but their expression fell when kidney damage became irreversible. These genes code for proteins that play a role in repairing DNA when it is damaged in cells. Additional experiments in mouse models of kidney injury and in human kidney biopsies confirmed the findings found in kidney organoids.

Finally, through drug testing, scientists identified a compound known as SCR7 that helped maintain FANCD2 and RAD51 activity to rescue normal tissue repair and prevent CRF progression in the researchers’ cisplatin-induced organoid injury model.

“We have shown that activating a DNA repair mechanism can help maintain healthy kidney status,” says lead author Ryuji Morizane, MD, PhD, senior researcher in the Division of Nephrology at the MGH. “In the future, this approach could become a new treatment option for patients with CKD.”

Other study authors include Takuya Matsumoto, Ken Hiratsuka, Edgar Garcia Saiz, Pierre Galichon, Tomoya Miyoshi, Koichiro Susa, Narihito Tatsumoto, and Michifumi Yamashita.

This work was supported by a National Institutes of Health (NIH) T32 Training Fellowship, a Harvard Stem Cell Institute Interdisciplinary Fellowship, two Brigham and Women’s Hospital Research Excellence Awards, a Cell Science Research Foundation Award, an NCATS UCLA CTSI Fellowship KL2, a Cedars-Sinai CTSI Clinical Scholar Grant, a Brigham and Women’s Hospital Faculty Career Development Award, a Harvard Stem Cell Institute Seed Grant, a DiaComp Pilot & Feasibility Program, an NIH DP2EB029388 award, and an NIH U01EB028899 grant.

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Material provided by Massachusetts General Hospital. Note: Content may be edited for style and length.

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