AHA Scientific Sessions 2026 Abstract · Nov 2, 2026
Semaglutide and Physical Exercise Preserve Renal Function and Tubular Redox Homeostasis by Limiting NRF2 Nuclear Translocation in Diabetic Kidney Disease
By Oliveira Silva E, Garcia Villalba J, Lucas de Camargo M et al.
Introduction: Diabetic kidney disease (DKD) is not only a leading cause of chronic kidney failure, but also the major driver of cardiovascular morbidity in type 2 diabetes mellitus (T2DM), linking renal dysfunction to vascular injury, inflammation and oxidative stress. Although GLP-1 receptor agonists have emerged as cardiometabolic therapies with potential kidney benefits, the mechanisms underlying their renoprotective effects, particularly when combined with physical exercise, remain incompletely defined. We tested whether semaglutide combined with moderate physical exercise (PT) provides additive renoprotection in experimental T2DM involving the activation of NFR2 and whether semaglutide directly protects HK-2 proximal tubular cells exposed to high glucose. Methods: Male Wistar rats were assigned to control (Citrate), GLP-1RA, T2DM, T2DM+PT, T2DM+GLP-1RA and T2DM+PT+GLP-1RA. Interventions lasted 28 days. Renal function, renal hemodynamics, oxidative biomarkers and NRF2 by immunofluorescence ) were evaluated. HK-2 cells were cultured in normal or high glucose and treated with semaglutide and MTT, LDH, and TGF-β were measured. Results: T2DM increased serum creatinine and reduced inulin clearance comparing to controls. Combined therapy (T2DM+PT+GLP-1RA) improved both parameters. PT, semaglutide, and combined therapy lowered renal vascular resistance and increased renal blood flow. Combined therapy reduced urinary peroxides, lipid peroxidation, and nitrate, and partially restored thiols. Nuclear localization of NRF2 was predominant in the T2DM group when compared to the control group. In contrast, PT and combined therapy markedly reduced nuclear localization of NRF2, bringing it closer to the control group. T2DM increased renal IL-1β and TGF-β, while combined therapy reduced IL-1β to control-like levels and attenuated TGF-β. In HK-2 cells, high glucose increased MTT signal, LDH release, and TGF-β while semaglutide reduced these changes. Conclusion: Semaglutide combined with moderate physical exercise conferred renal protection, not only as a consequence of weight loss or glycemic control, but also by attenuating renal alterations associated with DKD. Untreated DKD induced a tubular redox-stress phenotype, marked by NRF2 nuclear translocation restricted to renal tubules rather than glomeruli, suggesting a compartment-specific activation of the Keap1-NRF2 stress-response axis. Semaglutide, alone or combined with physical exercise, prevented the tubular NRF2 nuclear translocation. The HK-2 proximal tubular cells essay showed to attenuate metabolic overactivation induced by high-glucose, cytotoxicity, nitrosative stress and TGF-β expression. Together, these findings suggest the proximal tubule as a key site of redox maladaptation in DKD and support semaglutide-based therapy as a strategy to preserve tubular redox homeostasis.