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Abstract: FR-PO398

Diabetic Kidney Disease (DKD)-Induced Cardiac Damage Is Characterized and Reduced by Standard-of-Care Treatment in a Translational Diet-Induced Hypertension-Accelerated Mouse Model of DKD

Session Information

  • Hypertension and CVD: Basic
    November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Hypertension and CVD

  • 1601 Hypertension and CVD: Basic


  • 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
  • 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

Recently, we developed a diet-induced hypertension-accelerated mouse model of diabetic kidney disease characterized by progressive loss of GFR. Since cardiovascular disease is the major cause of death in CKD, we investigated the occurence of cardiac damage in this model. Additionally, we studied the efficacy of combination therapy with an ACE-inhibitor (Lisinopril) and SGLT2-inhibitor (Dapagliflozin) on cardiac damage.


Male KKAy mice underwent uninephrectomy. After recovery mice received high fat diet (45% LARD) and drinking water with or without 50 mg/L LNNA (wk0). In the intervention study, at week 4, lisinopril (2,5 mg/kg/day; drinking water) and at week 8 dapagliflozin (5 and 20 mg/kg/day;foodadmix) treatment were started. At week 16 mice were terminated and lung and heart weight and cardiac histology were determined.


Upon termination, macroscopic evaluation of the hearts showed extensive scar tissue formation on the outside of the left ventricle. Histological evaluation showed the presence left ventricular hypertrophy, coronary calcification and myocardial fibrosis in male KKAy mice with UNX, HFD and LNNA. KKAy mice with UNX and HFD but without LNNA also showed myocardial fibrosis, monocyte infiltration and focal mineralization.
Treatment with combination therapy reduced lung wet weight, significantly reduced heart weight and significantly decreased cardiac fibrosis. Macroscopically, less scar tissue was observed after treatment.


Cardiac damage is a clear feature in the KKAy mouse model of DKD, either with or without hypertension induction. Combination therapy with Lisinopril and Dapagliflozin reduced cardiac weight and cardiac fibrosis. This indicates cardiac involvement in the DKD mouse model which is clinically relevant. Studies functionally characterizing cardiac damage are currenlty ongoing.

Combination therapy with Lisinopril and Dapagliflozin shows reduced lung and heart weight and inhibited cardiac fibrosis.


  • Commercial Support – Janssen, BPM