"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."
"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."
Diabetic kidney disease drives chronic kidney disease and end-stage renal failure worldwide. SGLT2 inhibition elevates S-adenosylmethionine (SAM) levels in kidneys, correlating with improved renal function and decreased NF-κB inflammatory gene activity. Injured proximal tubular cells exhibit reduced MAT2A expression, the enzyme that synthesizes SAM. Blocking MAT2A in SGLT2-deficient mice eliminates the renal protection, confirming SAM’s essential role. SAM acts as a molecular switch that dampens inflammation by altering gene reading through epigenetic modification. Modulation of the MAT2A–SAM axis appears to underlie SGLT2 inhibitor kidney benefits and offers a potential therapeutic target.
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