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Abstract: FR-PO357

Kidney Disease Progression in Obese ZSF1 Rats Treated with the SGLT2 Inhibitor Empagliflozin

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Hummelgaard, Sandra, Aarhus Universitet, Aarhus, Midtjylland, Denmark
  • Kirchhoff, Jeppe, Novo Nordisk A/S, Bagsvaerd, Hovedstaden, Denmark
  • Hvid, Henning, Novo Nordisk A/S, Bagsvaerd, Hovedstaden, Denmark
  • Glerup, Simon, Aarhus Universitet, Aarhus, Midtjylland, Denmark
  • Birn, Henrik, Aarhus Universitetshospital, Aarhus, Denmark
  • Weyer, Kathrin, Aarhus Universitet, Aarhus, Midtjylland, Denmark
Background

The obese ZSF1 rat is a model of spontaneous diabetic kidney disease. These rats are bred from a zucker diabetic fatty female and a spontaneous hypertensive heart failure male and carry two mutations in the leptin receptor gene: LeprfaLeprcp/Crl. The control model for this rat is the lean ZSF1 rat (Leprfa/Crl). In contrast to many other animal models of kidney disease, the obese ZSF1 rat model is a slow progressing kidney disease model.
In this study, we evaluated kidney disease progression in obese ZSF1 rats and for the first time investigated renal outcomes upon treatment with the SGLT2 inhibitor empagliflozin.

Methods

Lean and obese ZSF1 rats were fed with Purina #5008 diet. In the first sub-study, lean and obese animals were left untreated and regular plasma and urine samples were collected for 36 weeks. In the second sub study, obese animals were treated with empagliflozin (in feed, estimated intake: 30 mg/kg/day) or vehicle at 14 weeks of age for 15 weeks. Plasma and urine samples were collected bimonthly or monthly, respectively. Glomerular filtration rate (GFR) was measured at baseline and upon 14 weeks of treatment. Plasma and urine samples were analyzed for lipid and kidney injury markers using COBAS analysis as well as various ELISAs. Histological analyses were performed on liver and kidney tissue.

Results

Plasma cholesterol, triglycerides, glucose as well as proteinuria increased with age in obese ZSF1 rats. Urinary excretion of the kidney injury markers KIM-1 and NGAL were also elevated with age, reaching maximum concentration at age 34 weeks. Histological analyses revealed severe glomerular damage at 46 weeks of age compared to lean controls.
SGLT2 inhibition with empagliflozin indeed reduced plasma glucose and triglyceride levels whereas urine volume and urinary glucose excretion were elevated.

Conclusion

Obese ZSF1 rats were hyperglycemic and hypercholesterolemic. Proteinuria increased with age in these rats, and severe glomerular damage was observed at 46 weeks of age. Empagliflozin reduced blood glucose and increased urine volume as well as glucose excretion. Future analyses investigating proteinuria, GFR as well as histological characteristics of kidney tissue are ongoing and warranted to evaluate renal outcomes upon empagliflozin treatment in obese ZSF1 animals.

Funding

  • Commercial Support – Novo Nordisk A/S