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Abstract: SA-PO435

Combination Therapy with Lisinopril and Dapagliflozin Rescues GFR Decline and Glomerular Damage in the KKAy Mouse Model of Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Van Koppen, Arianne, TNO, Leiden, South Holland, Netherlands
  • Nawrocki, Andrea R., Janssen Research and Development LLC, Boston, Massachusetts, United States
  • Hinke, Simon A., Janssen Research and Development LLC, Boston, Massachusetts, United States
  • van Goor, Harry, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands
  • Bajema, Ingeborg M., Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands
  • Dendooven, Amélie, Universitair Ziekenhuis Gent, Gent, Oost-Vlaanderen, Belgium
  • Nguyen, Tri Q., Universitair Medisch Centrum Utrecht Afdeling Pathologie, Utrecht, Utrecht, Netherlands
  • Breyer, Matthew Douglas, Janssen Research and Development LLC, Boston, Massachusetts, United States
  • Stoop, Reinout, TNO, Leiden, South Holland, Netherlands
Background

We previously showed that male KKAy mice develop DKD with progressive decline of GFR upon high fat diet feeding together with a vasoconstrictor. In this study, efficacy of combination therapy with an ACE-inhibitor (lisinopril) and SGLT2-inhibitor (dapagliflozin) on renal function and histopathology was investigated.

Methods

Male KKAy mice underwent uninephrectomy (UNX). After recovery mice received high fat diet (45% LARD) and 50 mg/L LNNA in drinking water (wk0). At week 4, lisinopril (2.5 mg/kg/day and at week 8 dapagliflozin (5 and 20 mg/kg/day) were started. Body weight, blood glucose, food and water intake and albuminuria were determined regularly. GFR was measured transdermally by FITC-sinistrin clearance. Mice were terminated at week 16 and kidney histology was scored. Non-induced and induced non-treated mice were used as controls.

Results

Treatment of KKAy mice on HFD+LNNA with Dapagliflozin reduced blood glucose immediately. Combination therapy with lisinopril and dapagliflozin (5 mg/kg/day) rescued the progressive GFR decline to levels seen in non-induced chow-controls. Pathology showed that the percentage of healthy glomeruli increased from 14% to 26% after combination therapy (dapa 5). Interstitial fibrosis and tubular atrophy were signficantly reduced by combination therapy.

Conclusion

Male KKAy mice on a HFD and LNNA developed DKD resulting in CKD. Combination therapy with Lisinopril and Dapagliflozin rescued GFR decline and reduced glomerular damage. This indicates that the model is clinically relevant and can be used to study compound efficacy in both early and more advanced stages of DKD.

Figure 1: Dapagliflozin decreased blood glucose levels. Combination therapy with Lisinopril and Dapagliflozin rescued GFR decline, glomerular damage and interstitial fibrosis and tubular atrophy.

Funding

  • Commercial Support – Janssen, BPM