Abstract: FR-PO0160
Semaglutide Attenuates Proteinuria and Tubular Injury in the ZSF1 Model of Diabetic Kidney Disease
Session Information
- Diabetic Kidney Disease: Metabolic, Mitochondrial, and Inflammatory Mechanisms
October 23, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Cardiovascular-Kidney-Metabolic Health
- 601 Cardiovascular-Kidney-Metabolic Health: Basic
Authors
- Poling, Brent, Eli Lilly and Company, Indianapolis, Indiana, United States
- Porras, Leah L., Eli Lilly and Company, Indianapolis, Indiana, United States
- Politan, Taylor K., Eli Lilly and Company, Indianapolis, Indiana, United States
- Badger, Hannah S., Eli Lilly and Company, Indianapolis, Indiana, United States
- Badal, Shawn S., Eli Lilly and Company, Indianapolis, Indiana, United States
- Dey, Asim, Eli Lilly and Company, Indianapolis, Indiana, United States
Background
Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease globally, with GLP-1 receptor agonists recently demonstrating promising renal benefits. Despite emerging evidence supporting GLP-1R-mediated renoprotection across clinical and preclinical settings, the mechanisms underlying renal disease attenuation in preclinical models remain poorly defined. Here, we report the first characterization of semaglutide's renal effects in the Zucker Spontaneously Fatty 1 (ZSF1) obese rat, a progressive preclinical model of obesity and diabetic kidney disease.
Methods
Male ZSF1 lean and obese rats (ZSF1-LeprfaLeprcp/Crl) were stratified at 28 weeks of age into three groups based on fasted blood glucose, body weight, and urinary Protein-Creatinine-Ratio: lean vehicle (n=6), obese vehicle (n=12), and Semaglutide (Sema) 10 nmol/kg, once daily, (n=12). Urine was collected over 24 hours on days 14 and 28 using metabolic cages, and 4-hour fasted blood glucose was measured by glucometer at 1, 7, 21, and 43 days post dose.
Results
Following Semaglutide treatment, significant reductions were observed in food intake (369 vs. 465 g/week, p<0.001) and fasting glucose (189 vs. 347 mg/dL, p<0.001) compared to vehicle. Semaglutide significantly attenuated body weight gain (0% vs. 3% change from baseline, p<0.005). Importantly, Sema attenuated progressive increase in proteinuria compared to vehicle(uPCR: 21.8 vs. 40.3 mg/mg, p<0.001). Urinary injury biomarkers demonstrated a significant decrease following Sema treatment compared to vehicle (Kidney Injury Marker 1 (KIM1: 20.3 vs 52.1 ng/mg, p<0.0001), Lipocalin-2 (NGAL: 495 vs 893 ng/mg, p<0.001), and Tumor Necrosis Factor Receptor-II (TNFRII 554 vs 993 pg/mg, p<0.0001)). Preliminary histological analysis revealed a significant improvement in tubular degeneration/regeneration following semaglutide treatment compared to vehicle (Score: 2.25 vs 2.83, p<0.05).
Conclusion
In the ZSF1 model of DKD, semaglutide reduced proteinuria and tubular injury markers alongside metabolic benefits, consistent with clinical observations. Future studies delineating the cell-specific and molecular mechanisms underlying these effects will be critical to understanding how metabolic therapeutics can modulate renal disease outcomes.