A new Northwestern Medicine study has shed light on how a class of diabetes drugs may protect the kidneys — not just by lowering blood sugar, but by triggering a molecular shift that dampens inflammation, according to the study published in The Journal of Clinical Investigation.
Diabetic kidney disease is a leading cause of chronic kidney disease and end-stage kidney failure worldwide. A relatively new class of drugs, known as sodium–glucose co-transporter 2 (SGLT2) inhibitors, which were initially developed to improve glucose control, have demonstrated powerful benefits in previous clinical trials, said Hiroshi Maekawa, MD, PhD, who was first author of the study and a visiting investigator in the laboratory of the study’s senior author, Susan Quaggin, MD, chair and the Irving S. Cutter Professor of Medicine.
“We already know that SGLT2 inhibitors slow kidney damage in people with diabetes and kidney diseases,” Maekawa said. “But no one really understood why blocking a single transporter in the kidney had such a large protective effect.”
In the study, investigators observed mice on a high-fat diet. They found that mice lacking SGLT2 function had elevated levels of a key molecule, S-adenosylmethionine (SAM), in their kidneys. This increase in SAM was associated with improved kidney function and reduced activity in genes linked to the NF-κB inflammatory pathway, a known driver of kidney damage.
The scientists then explored the cellular and genetic landscape of kidney tissue, revealing that injured proximal tubular cells — common in diabetic kidney disease — showed reduced expression of the enzyme MAT2A, which is responsible for producing SAM. When investigators inhibited MAT2A in SGLT2-deficient mice, kidney protection was lost, confirming SAM’s critical role.
“This molecule acts as a switch, turning down inflammation by changing the way genes are read through a process called epigenetic modification,” Maekawa said. “The benefit of SGLT2 inhibition isn’t just about sugar control, it’s also about rewiring the metabolism to keep inflammation in check.”
Further analysis, conducted in collaboration with study co-authors Yuki Aoi, PhD, assistant professor of Medicine and of Biochemistry and Molecular Genetics, and Ali Shilatifard, PhD, the Robert Francis Furchgott Professor and chair of Biochemistry and Molecular Genetics, who were co-authors of the study, revealed that SAM’s presence resulted in increased trimethylation of histone H3K27 at inflammatory genes. This modification, known to repress gene expression, appears to be a key mechanism by which SGLT2 inhibition shields the kidneys from metabolic stress, Maekawa said.
By blocking glucose reabsorption in the kidneys, SGLT2 inhibitors may elevate SAM levels, which in turn suppress inflammatory gene activity, Maekawa said. This discovery could pave the way for more targeted therapies to slow kidney disease progression in people with diabetes.
“This work opens a new chapter in kidney research,” Maekawa said. “Our research shows that SGLT2 inhibition rewires the kidney metabolism and gene activity, uncovering a new way: the kidney defense itself. This raises the possibility of some exciting new therapeutic avenues that will inspire us to keep investigating.”
Reflecting on the team effort, Maekawa added, “This study is a wonderful demonstration of the culture of collaboration that exists at Northwestern — Ali Shilatifard and Yuki Aoi (Department of Biochemistry), Nav Chandel and his team (Metabolism and Molecular Genetics) and Joe Bass and his team (Diabetes and Metabolism) were critical to move this story forward.”
The study was supported by a pilot award from the Northwestern University George M. O’Brien Kidney Resource Core Center (NUGoKidney, NIH/NIDDK U54DK137516), National Institutes of Health-funded programs (R01EY025799-05, U54 DK137307, U2CDK129917 and TL1DK132769), an American Heart Association-funded program (24SFRNCCN1276086) and a fellowship program from Takeda Science Foundation.
