Abstract: SA-PO112
Dapagliflozin Reduces Glomerular Hyperfiltration and Improves Urine Parameters in db/db Mice on High Protein Diet: A 4-week Model of Diabetic Nephropathy
Session Information
- Diabetic Kidney Disease: Basic - III
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Briand, Francois, Physiogenex SAS, Labege, France
- Nørgaard, Sisse Andersen, Novo Nordisk A/S, Maaloev, Denmark
- Burr, Noémie, Physiogenex SAS, Labege, France
- Costard, Clément, Physiogenex SAS, Labege, France
- Brousseau, Emmanuel, Physiogenex, Labege, France
- Faresse, Nourdine, Physiogenex SAS, Labege, France
- Wolfhagen Sand, Fredrik, Novo Nordisk A/S, Maaloev, Denmark
- Sulpice, Thierry, Physiogenex SAS, Labege, France
Background
Preclinical animal models of glomerular hyperfiltration and diabetic nephropathy (DN) are needed for rapidly evaluating novel drugs targeting these complications. In this goal, obese and diabetic db/db mice are routinely used, but require several weeks to only show mild-albuminuria and early kidney disorders seen in human DN. Since high protein diet (HPD) are known to accelerate DN in human and animal models, we therefore developed a 4-week HPD fed db/db mouse model, in which the sodium glucose cotransporter 2 inhibitor dapagliflozin (DAPA) was evaluated.
Methods
12-week old db/db male mice were placed on a HPD (60%kcal from protein) and treated with vehicle or DAPA 10mg/kg orally once daily for 4 weeks. Non-diabetic db/+ males on HPD treated with vehicle were included as negative control. Oral glucose tolerance test (OGTT), biochemical assays and glomerular filtration rate (GFR), assessed with FITC-sinistrin i.v. injection and transdermal monitors, were performed.
Results
Compared to db/+, db/db mice on HPD were strongly hyperglycemic, showed increased urine glucose excretion (UGE), higher albuminuria (+127%), and evident hyperfiltration, with a 40% higher GFR vs. db/+ (p<0.05 for all parameters).
Compared to db/db treated with vehicle, DAPA blunted hyperglycemia in fasting state and during the OGTT (73% reduction in glucose area under the curve) and strongly increased fasting plasma ketone levels by 300% (all p<0.001). As expected, DAPA increased UGE by 116% (p<0.01 vs. vehicle) and reduced albumin/creatinine ratio by 40%, although not significantly.
Compared with vehicle, DAPA reduced proteinuria and creatinine clearance by 36% (p<0.001) and 45% (p<0.05). Additionally, DAPA significantly reduced hyperfiltration with a 12% and 21% reduction in GFR at 2 and 4 weeks of treatment, respectively.
Conclusion
The present data indicate that DAPA shows significant benefits on kidney dysfunction in the 4-week HPD fed db/db mouse model. This fast model should be useful to rapidly evaluate drugs targeting diabetic nephropathy and glomerular hyperfiltration.
Funding
- Commercial Support – PHYSIOGENEX SAS