Ceramides had been recognized because the molecular culprits behind acute kidney harm, damaging mitochondria and resulting in organ failure.
Blocking ceramide metabolism fully protected kidneys in mice, providing hope for treating AKI and associated illnesses.
Ceramides a Key Set off for Acute Kidney Harm
Acute kidney harm (AKI) is a sudden lack of short-term kidney operate that may be deadly and might increase the chance of everlasting persistent kidney illness. Triggers embrace extreme infections corresponding to sepsis and main procedures like coronary heart surgical procedure, and the situation strikes greater than half of sufferers in intensive care items. No accepted medicines presently deal with AKI.
Researchers at College of Utah Well being (U of U Well being) report that fatty molecules known as ceramides set off AKI by harming mitochondria inside kidney cells. In mouse experiments, a backup drug candidate that alters how ceramides are processed protected mitochondrial construction and prevented kidney harm.
Reversing Kidney Injury:
“We fully reversed the pathology of acute kidney harm by inactivating ceramides,” says Scott Summers, PhD, distinguished professor and Chair of the Division of Diet and Integrative Physiology within the College of Utah School of Well being and senior writer on a paper describing the outcomes. “We had been surprised—not solely did kidney operate keep regular, however the mitochondria had been unscathed,” Summers says. “It was actually outstanding.”
The outcomes had been revealed at this time (November 12) in Cell Metabolism.
An Early Warning Signal for Kidney Harm
The Summers lab had beforehand proven that ceramides can injure a number of organs, together with the center and liver. When the workforce measured ceramides in fashions of AKI, ranges climbed steeply after kidney harm in each mice and human urine samples.
“Ceramide ranges are very elevated in kidney harm,” says Rebekah Nicholson, PhD, first writer on the examine, who did the analysis as a graduate scholar in diet and integrative physiology at U of U Well being and is now a postdoctoral fellow on the Arc Institute. “They go up shortly after harm to the kidneys, and so they go up in relation to the severity of the harm. The more severe the kidney harm is, the upper the ceramide ranges might be.”
These outcomes point out that urinary ceramides may function an early biomarker for AKI, serving to clinicians flag high-risk sufferers earlier than signs emerge, together with individuals present process coronary heart surgical procedure. “If sufferers are present process a process that we all know places them at excessive threat of AKI, then we are able to higher predict whether or not or not they’re really going to have one,” Nicholson says.
Modifying Ceramides Prevents Kidney Harm
By exactly altering the genetic program that produces ceramides, the workforce created mice that resisted AKI even underneath situations that usually trigger it. These “tremendous mice” remained protected regardless of sturdy experimental stressors.
Preventive therapy with a brand new ceramide-lowering drug candidate from Centaurus Therapeutics, an organization co-founded by Summers, additionally blocked kidney harm in mice. Kidney operate improved, the animals stayed lively, and kidney tissue appeared near regular underneath a microscope. The analysis mannequin places important pressure on the kidneys, Nicholson notes, so “it’s actually outstanding that mice had been shielded from the harm.”
“These mice seemed unimaginable,” Summers provides.
The investigators decided that ceramides harm mitochondria, the mobile constructions that generate power. In injured kidney cells, mitochondria grow to be misshapen and fewer environment friendly. Adjusting ceramide synthesis, both by genetics or with the drug, maintained wholesome, working mitochondria even throughout stress.
Hope for Acute Kidney Harm and Past
Summers notes that the compound used on this examine is intently associated to, however distinct from, the ceramide-lowering drug already transferring into human trials. He emphasizes that mouse information don’t at all times predict outcomes in individuals and that security should be established with additional testing.
“We’re thrilled by how protecting this backup compound was, nevertheless it’s nonetheless preclinical,” Summers says. “We must be cautious and do our due diligence to ensure this strategy is really protected earlier than transferring it into sufferers.”
If the outcomes translate to individuals, the workforce envisions giving the remedy forward of time to people at excessive threat for AKI, corresponding to these scheduled for coronary heart surgical procedure, a bunch during which about one quarter expertise AKI.
As a result of the strategy seems to work by preserving mitochondrial well being, the researchers suspect it may have worth for different situations linked to impaired mitochondria.
“Mitochondrial issues present up in so many illnesses—coronary heart failure, diabetes, fatty liver illness,” Summers says. “So if we are able to actually restore mitochondrial well being, the implications could possibly be monumental.”
Reference: “Therapeutic Reworking of the Ceramide Spine Prevents Kidney Harm” 12 November 2025, Cell Metabolism.
DOI: 10.1016/j.cmet.2025.10.006
This analysis obtained assist from a number of organizations, together with an NCRR Shared Instrument Grant, the Kidney Precision Drugs Challenge, and several other branches of the National Institutes of Health. Funding was provided by the National Cancer Institute (P30CA042014, CA272529), the National Institute of Diabetes and Digestive and Kidney Diseases (DK115824, DK116888, DK116450, DK130296, DK108833, DK112826, 1F31DK134088, and 5T32DK091317), and the National Institute of General Medical Sciences (3R35GM131854 and 3R35GM131854-04S1). Additional support came from the Juvenile Diabetes Research Foundation (JDRF 3-SRA-2019-768-A-B, awarded to WLH), the Burroughs Wellcome Fund Postdoctoral Diversity Enrichment Program (1058616), the American Diabetes Association, the American Heart Association, the Margolis Foundation, and the University of Utah Diabetes and Metabolism Research Center.
Scott Summers and Jeremy Blitzer are co-founders and shareholders of Centaurus Therapeutics. Liping Wang is also a shareholder of Centaurus Therapeutics. DN and Blitzer are named as inventors on U.S. Patents 1177684, 11597715, and 11135207, which are licensed to Centaurus Therapeutics, Inc.
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