Serious damage to short-term kidney function-known as acute kidney injury (AKI) can be fatal and also increase the risk of irreversible chronic kidney disease. It can be triggered by stressors ranging from sepsis to heart surgery, and it affects more than half of ICU patients. There are currently no drugs to treat AKI. Now, researchers at University of Utah Health have found that AKI is triggered by fatty molecules called ceramides, which cause serious injury by damaging kidney mitochondria. Using a backup drug candidate that changes ceramide metabolism, the team was able to preserve mitochondrial integrity and prevent kidney injury in mice. The research lab, led by professor Summers had previously shown that ceramides can damage tissues ranging from heart to liver.
When the team profiled ceramides in models of AKI, the correlation was striking: ceramide levels spiked sharply after kidney injury in both mice and human urine samples. These findings suggest that urinary ceramide levels could serve as an early biomarker for AKI, helping doctors identify patients at risk – such as those undergoing heart surgery – before symptoms appear. The researchers were able to almost completely prevent kidney injury in an animal model by changing how ceramides are made. Ceramide actions were dependent on the presence of the 4,5-trans double bond inserted by dihydroceramide desaturase 1 (DES1). Genetically ablating DES1 preserved mitochondrial integrity and prevented kidney injury in mice following bilateral ischemia reperfusion.
By making a precise genetic change that affects ceramide production, the team created “super mice” that don’t get AKI, even in conditions that would otherwise trigger it. Similarly, pre-treating mice with a new ceramide-lowering drug candidate developed by Centaurus Therapeutics, a company co-founded by Summers, prevented kidney injury. Kidney function improved, mice stayed fully active and the kidneys looked nearly normal under the microscope. Ceramides cause kidney injury by damaging mitochondria, that produces energy, the researchers found. Mitochondria in injured kidney cells are visibly malformed under a microscope, and they can’t efficiently produce energy. Tweaking how ceramides are made kept mitochondria functional even under stress.
Summers emphasizes that the compound used in the study is closely related to, but not the same as, the ceramide-lowering drug that has advanced into human clinical testing. Results in mice don’t always translate directly to humans, he notes, and additional studies are needed to establish safety. But the researchers are optimistic. If the results hold true in humans, the researchers hope that the drug could be provided in advance to people at high risk of acute kidney injury-such as people undergoing heart surgery, about a quarter of whom experience AKI. Because the drug seems to work by keeping mitochondria healthy, the researchers suspect that it might help treat or prevent many other diseases that affect mitochondria.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Nicholson NJ et al. Cell Metabolism 2025 Nov 12; in press.
Morita Y, Sakai E et al. Front. Nephrol. 2024; 4:1343181
Wilkerson JL, Tatum SM et al. Physiol Rev. 2024; 104:1061.
Liang L, Li D et al. Cardiovasc Diabetol. 2023; 22:92.
