Abstract: FR-PO0305
Exploration of Cagrilintide's Mechanism of Action in the Kidneys
Session Information
- Diabetic Kidney Disease: Basic and Translational Science Advances - 1
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
Authors
- Wulfmeyer, Vera Christine, Aarhus Universitet, Aarhus, Central Denmark Region , Denmark
- Billing, Anja M., Aarhus Universitet, Aarhus, Central Denmark Region , Denmark
- Bhayana, Sagar, Novo Nordisk A/S, Copenhagen, Capital Region of Denmark, Denmark
- Østergaard, Mette Viberg, Novo Nordisk A/S, Copenhagen, Capital Region of Denmark, Denmark
- Rinschen, Markus M., Aarhus Universitet, Aarhus, Central Denmark Region , Denmark
Background
The hormone amylin, co-secreted with insulin from the beta-cells of the pancreas, induces satiety. Previous studies have highlighted a physiological role of amylin in glucose/sodium homeostasis and blood pressure regulation. Cagrilintide, a long-acting amylin analogue, which binds to both calcitonin and amylin receptors (G-protein-coupled receptors), has demonstrated a significant effect on weight loss in humans. Despite this, the kidney-specific metabolic pathways affected by amylin agonism remain poorly understood. To address this gap, we investigated cagrilintide’s mechanism of action in the kidneys of healthy and diabetic Zucker Diabetic Fatty (ZDF) rats using an ex vivo approach.
Methods
The kidneys of male ZDF rats, 13 to 15 weeks in age (10 obese/diabetic and 10 lean/healthy), underwent digestion into cortical and medullary tubule fractions. Tubules were exposed to a phosphodiesterase inhibitor and then treated with vehicle, cagrilintide, or salmon calcitonin for 30min. Intracellular cyclic AMP (cAMP) levels were quantified using a commercially available detection kit. Residual tubular samples were snap-frozen for subsequent phosphoproteomics.
Results
In healthy rat tubules, cagrilintide induced phosphorylation of ion transporters in the thick ascending limb of the loop of Henle and the distal convoluted tubule (e.g., NKCC2 and NCC), while also modifying mTOR regulators. Obese ZDF rats proved to be diabetic with a mean HbA1c of 7.2%, and demonstrated evidence of diabetic nephropathy, characterized by glomerular hyperfiltration and severely increased albuminuria. In these diabetic ZDF rats, cagrilintide significantly increased intracellular cAMP levels in cortical tubules. Preliminary findings suggest that the distal nephron in diabetic rats may be more responsive to cagrilintide. Phosphoproteomic measurements are ongoing and expected to reveal downstream signaling alterations modulated by cagrilintide in nephron segments.
Conclusion
Our results point to a diabetes-specific mechanism by which cagrilintide elevates cAMP in cortical tubules, providing initial evidence of mode of action in diabetic kidney physiology compared with healthy controls. Ongoing phosphoproteomic analyses will offer deeper insights into the molecular pathways affected, potentially guiding the therapeutic application of cagrilintide in diabetic kidney disease.
Funding
- Commercial Support – Novo Nordisk, Denmark