Potential Breakthrough In Treating Acute Kidney Injury With Ceramide-targeting Drugs

Serious harm to short-term kidney function-known arsenic acute kidney injury, aliases AKI-can beryllium fatal and besides summation nan consequence of irreversible chronic kidney disease. It tin beryllium triggered by stressors ranging from sepsis to bosom surgery, and it affects much than half of ICU patients. There are presently nary narcotics to dainty AKI.

Now, researchers astatine University of Utah Health (U of U Health) person recovered that AKI is triggered by fatty molecules called ceramides, which origin superior wounded by damaging kidney mitochondria. Using a backup supplier campaigner that changes ceramide metabolism, nan squad was capable to sphere mitochondrial integrity and forestall kidney wounded successful mice.

"We wholly reversed nan pathology of acute kidney wounded by inactivating ceramides," says Scott Summers, PhD, distinguished professor and Chair of nan Department of Nutrition and Integrative Physiology successful nan University of Utah College of Health and elder writer connected a insubstantial describing nan results. "We were stunned-not only did kidney usability enactment normal, but nan mitochondria were unscathed," Summers says. "It was genuinely remarkable."

The results are published successful Cell Metabolism.

An early informing motion for kidney injury

The Summers laboratory had antecedently shown that ceramides tin harm tissues ranging from bosom to liver. When nan squad profiled ceramides successful models of AKI, nan relationship was striking: ceramide levels spiked sharply aft kidney wounded successful some mice and quality urine samples.

"Ceramide levels are very elevated successful kidney injury," says Rebekah Nicholson, PhD, first writer connected nan study, who did nan investigation arsenic a postgraduate student successful nutrition and integrative physiology astatine U of U Health and is now a postdoctoral chap astatine nan Arc Institute. "They spell up quickly aft harm to nan kidneys, and they spell up successful narration to nan severity of nan injury. The worse nan kidney wounded is, nan higher nan ceramide levels will be."

These findings propose that urinary ceramide levels could service arsenic an early biomarker for AKI, helping doctors place patients astatine risk-such arsenic those undergoing bosom surgery-before symptoms appear. "If patients are undergoing a process that we cognize puts them astatine precocious consequence of AKI, past we tin amended foretell whether aliases not they're really going to person one," Nicholson says.

Modifying ceramides prevents kidney injury

The researchers were capable to almost wholly forestall kidney wounded successful an animal exemplary by changing really ceramides are made. By making a precise familial alteration that affects ceramide production, nan squad created "super mice" that don't get AKI, moreover successful conditions that would different trigger it.

Similarly, pre-treating mice pinch a caller ceramide-lowering supplier campaigner developed by Centaurus Therapeutics, a institution co-founded by Summers, prevented kidney injury. Kidney usability improved, mice stayed afloat active, and nan kidneys looked astir normal nether nan microscope. The exemplary nan researchers usage tends to put nan kidneys nether a batch of stress, Nicholson says, truthful "it's really singular that mice were protected from nan injury."

 "These mice looked incredible," Summers adds.

Ceramides origin kidney wounded by damaging mitochondria, nan portion of nan compartment that produces energy, nan researchers found. Mitochondria successful injured kidney cells are visibly malformed nether a microscope, and they can't nutrient power arsenic efficiently. Tweaking really ceramides are made, either genetically aliases pinch nan drug, kept mitochondria patient and functional moreover nether stress.

Hope for acute kidney wounded and different diseases

Summers emphasizes that nan compound utilized successful nan study is intimately related to, but not nan aforesaid as, nan ceramide-lowering supplier that has precocious into quality objective testing. Results successful mice don't ever construe straight to humans, he notes, and further studies are needed to found safety.

We're thrilled by really protective this backup compound was, but it's still preclinical. We request to beryllium cautious and do our owed diligence to make judge this attack is genuinely safe earlier moving it into patients."

Scott Summers, PhD, distinguished professor and Chair of nan Department of Nutrition and Integrative Physiology, University of Utah College of Health

But nan researchers are optimistic. If nan results clasp existent successful humans, nan researchers dream that nan supplier could beryllium provided successful beforehand to group astatine precocious consequence of acute kidney injury-such arsenic group undergoing bosom surgery, astir a 4th of whom acquisition AKI.

Because nan supplier seems to activity by keeping mitochondria healthy, nan researchers fishy that it mightiness thief dainty aliases forestall galore different diseases that impact mitochondria.

"Mitochondrial problems show up successful truthful galore diseases-heart failure, diabetes, fatty liver disease," Summers says. "So if we tin genuinely reconstruct mitochondrial health, nan implications could beryllium enormous."

The results are published successful Cell Metabolism as "Therapeutic Remodeling of nan Ceramide Backbone Prevents Kidney Injury."

The activity was supported by a NCRR Shared Instrument Grant, nan Kidney Precision Medicine Project, nan National Institutes of Health, including nan National Cancer Institute (grants P30CA042014, CA272529), nan National Institute of Diabetes and Digestive and Kidney Diseases (grants DK115824, DK116888, DK116450, DK130296, DK108833, DK112826, 1F31DK134088 and 5T32DK091317), nan National Institute of General Medical Sciences (grants 3R35GM131854 and 3R35GM131854-04S1), nan Juvenile Diabetes Research Foundation (JDRF 3-SRA-2019-768-A-B and JDRF 3-SRA-2019-768-A-B to WLH), nan Burroughs Wellcome Fund for Postdoctoral Diversity Enrichment Program (1058616), nan American Diabetes Association, nan American Heart Association, nan Margolis Foundation, and nan University of Utah Diabetes and Metabolism Research Center. The contented is solely nan work of nan authors and does not needfully correspond nan charismatic views of nan National Institutes of Health.

Scott Summers and Jeremy Blitzer are co-founders and shareholders of Centaurus Therapeutics. Liping Wang is simply a shareholder of Centaurus Therapeutics. DN and Blitzer are listed arsenic inventors connected US Patents 1177684, 11597715, and 11135207 licensed to Centaurus Therapeutics, Inc.