Scientists Uncover a New Way to Reverse Kidney Damage in Mice, Offering Hope for Humans
Kidney damage, or acute kidney injury (AKI), is a serious condition that can be life-threatening and increase the risk of permanent chronic kidney disease. It often occurs after major stressors like sepsis or heart surgery, affecting more than half of intensive care patients. Currently, there are no approved medications to treat this condition.
Researchers at the University of Utah Health (U of U Health) have made a groundbreaking discovery. They found that fatty molecules called ceramides initiate AKI by damaging the mitochondria, which supply energy to kidney cells. By using a backup drug candidate designed to alter ceramide processing, the team successfully protected mitochondrial structure and prevented kidney injury in mice.
"We completely reversed the pathology of acute kidney injury by inactivating ceramides," says Scott Summers, PhD, distinguished professor and chair of the Department of Nutrition and Integrative Physiology at U of U Health. "We were stunned -- not only did kidney function stay normal, but the mitochondria were unscathed. It was truly remarkable."
The study's findings were published in Cell Metabolism.
Ceramide Spikes as an Early Warning Sign
Previous studies from the Summers lab have shown that ceramides can harm organs like the heart and liver. When researchers measured ceramides in AKI models, they found a strong connection: levels rose sharply after injury in both mice and human urine samples.
"Ceramide levels are very elevated in kidney injury," says Rebekah Nicholson, PhD, first author of the study. "They go up quickly after damage to the kidneys, and they go up in relation to the severity of the injury. The worse the kidney injury is, the higher the ceramide levels will be."
These findings suggest that urinary ceramides could act as an early biomarker for AKI, allowing clinicians to identify vulnerable patients before symptoms begin. This is particularly important for patients undergoing procedures like heart surgery, where the risk of AKI is high.
Altering Ceramide Production Protects Kidney Function
The team nearly eliminated kidney injury in a mouse model by modifying the genetic program that controls ceramide production. They created "super mice" that did not develop AKI even under conditions that typically cause severe damage.
The researchers then tested a ceramide-lowering drug candidate created by Centaurus Therapeutics, a company co-founded by Summers. Mice treated ahead of time avoided kidney injury, maintained normal kidney function, remained active, and had kidneys that appeared close to normal under the microscope.
"These mice looked incredible," Summers adds.
The team found that ceramides harm mitochondria, the parts of the cell responsible for energy production. Damaged mitochondria in kidney cells become distorted and function poorly. Adjusting ceramide production, whether genetically or with the drug, kept mitochondria intact and working even under strain.
Potential for Future Therapies Targeting Mitochondrial Health
Summers explains that the compound used in this study is closely related to, but not identical to, the ceramide-lowering drug that has entered human clinical testing. He emphasizes that mouse results do not always predict human outcomes and that further research is needed to confirm safety.
"We're thrilled by how protective this backup compound was, but it's still preclinical," Summers says. "We need to be cautious and do our due diligence to make sure this approach is truly safe before moving it into patients."
Even so, the researchers are encouraged by the findings. If the results extend to people, the drug could potentially be administered ahead of time to individuals who face a high risk of AKI, including patients undergoing heart surgery, where about one quarter experience the condition.
Because the drug appears to work by maintaining mitochondrial health, the team believes that the approach may have relevance for other disorders linked to mitochondrial dysfunction.
"Mitochondrial problems show up in so many diseases -- heart failure, diabetes, fatty liver disease," Summers says. "So if we can truly restore mitochondrial health, the implications could be enormous."
The results were published in Cell Metabolism as "Therapeutic Remodeling of the Ceramide Backbone Prevents Kidney Injury."
Funding and Disclosures
This work was supported by various grants from the National Institutes of Health, including the National Cancer Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Institute of General Medical Sciences. Additional support came from several foundations and organizations, including the Burroughs Wellcome Fund and the American Diabetes Association.
The authors declare that the content is their responsibility and does not necessarily reflect the views of the funding organizations or any other entities.
