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Abstract: SA-PO833

Dapagliflozin vs. Ramipril Therapy in Mice with Alport Syndrome

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: From Inflammation to Fibrosis

Authors

  • Miyata, Kana N., Saint Louis University School of Medicine, Saint Louis, Missouri, United States
  • Li, Jian Ping, Saint Louis University School of Medicine, Saint Louis, Missouri, United States
  • Yeargin, Faith Andrea, Saint Louis University School of Medicine, Saint Louis, Missouri, United States
  • Yamashita, Michifumi, Cedars-Sinai Medical Center Department of Pathology & Laboratory Medicine, Los Angeles, California, United States
  • Zhang, Shao-Ling, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada
  • Chan, John S.D., Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada
  • Miner, Jeffrey H., Washington University in St Louis School of Medicine, St Louis, Missouri, United States
Background

Angiotensin-converting enzyme inhibitors (ACEi) have been the best studied treatment for Alport syndrome with established benefits for renal function and survival in animals and humans. Recent clinical trials have shown that sodium glucose cotransporter 2 inhibitors (SGLT2i) are a key disease-modifying therapy to prevent the progression of chronic kidney disease when used on a background of renin-angiotensin-aldosterone system (RAAS) blockade. The objective of this study is to investigate whether SGLT2i exerts renoprotection as much as ACEi in Alport syndrome.

Methods

We studied male Col4α3 knockout mice, an Alport syndrome model, on a 129S1/SvImJ background. Dapagliflozin (1.5 mg/kg/day) or Ramipril (10 mg/kg/day) were orally administered via drinking water, starting at 4 weeks of age to 10 weeks of age (N=6-8/group). Wild-type (WT) and Alport littermates received vehicle for the same duration and served as controls. Glomerular filtration rate (GFR) was measured by inulin-FITC clearance in conscious mice, and kidneys were processed for histology (PAS, Sirius Red staining).

Results

Alport mice treated with Dapagliflozin had enhanced glucose excretion in urine, but blood glucose level was not changed. At 10 weeks of age, Alport mice developed a significant weight loss, decreased GFR/body weight, and elevated BUN. These were attenuated by Ramipril, but not by Dapagliflozin. Histological analysis of Alport mouse kidneys showed global and segmental glomerulosclerosis, tubular casts and tubulointerstitial fibrosis, which were more consistently improved by Ramipril than by Dapagliflozin.

Conclusion

Ramipril had more favorable effects on preservation of renal function and renal architecture in Col43 knockout Alport mice than Dapagliflozin. Our head-to-head comparison indicates that SGLT2i may not be an alternative option for ACEi in glomerular diseases. Further studies are currently ongoing to investigate the effects of a higher dose of Dapagliflozin and of combined treatment of SGLT2i with RAASi.

Funding

  • Private Foundation Support