Abstract: SA-PO712
Dapagliflozin in Addition to Ramipril Ameliorates Kidney Disease Progression in Mice with Alport Syndrome
Session Information
- Glomerular Diseases: Therapeutic Strategies
October 26, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Miyata, Kana, Saint Louis University School of Medicine, St Louis, Missouri, United States
- Smith, Denise, Saint Louis University School of Medicine, St Louis, Missouri, United States
- Yamashita, Michifumi, Cedars-Sinai Medical Center, Los Angeles, California, United States
- Kim, Shimok, Saint Louis University School of Medicine, St Louis, Missouri, United States
- Yeargin, Faith Andrea, Saint Louis University School of Medicine, St Louis, Missouri, United States
- Beganovic, Melisa, Saint Louis University School of Medicine, St Louis, Missouri, United States
- Leal, Daniel N., Cedars-Sinai Medical Center, Los Angeles, California, United States
- Edwards, John C., Saint Louis University School of Medicine, St Louis, Missouri, 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, St Louis, Missouri, United States
Background
Renin-angiotensin-aldosterone system inhibitors (RAASi) have been the most extensively studied treatment for Alport syndrome, demonstrating established benefits for renal function and survival in both animals and humans. We presented that Ramipril (an angiotensin-converting enzyme inhibitor) had more renoprotective effects in mice with Alport syndrome than sodium glucose cotransporter 2 inhibitors, Dapagliflozin (ASN Kidney Week 2023). The objective of this study is to investigate whether combination treatment with Dapagliflozin and Ramipril exerts a better kidney-protective effect than treatment with Ramipril alone in Col4α3 knockout (KO) mice (an Alport syndrome model).
Methods
We studied both sexes of Col4α3 KO and wild-type (WT) mice (129S1/SvImJ background). Dapagliflozin (1.5 mg/kg/day), Ramipril (10 mg/kg/day), or a combination of both were orally administered via drinking water for 6 weeks, starting at 4 weeks of age (N=8-10/group). The control mice received vehicle for the same duration. Glomerular filtration rate (GFR) was measured by inulin-FITC clearance in conscious mice, and kidneys were processed for histology (PAS, Masson’s Trichrome staining and electron microscope). Another set of mice were monitored for their survival.
Results
At 10 weeks of age, Col4α3 KO mice developed a significant weight loss, decreased GFR/body weight, elevated BUN and urine albumin/creatinine ratio. These findings were attenuated by Ramipril, and further improved by the combination treatment. Histologically, Col4α3 KO kidneys showed the severe degree of global and segmental glomerulosclerosis, tubulointerstitial fibrosis, and thickened glomerular basement membrane, which were more significantly improved by the combination treatment than by Ramipril alone. Furthermore, the combination treatment prolonged the life of Col4α3 KO mice; median survival was 157 days in combination treatment while 127 days in Ramipril alone (p<0.01).
Conclusion
The combination of Dapagliflozin and Ramipril had more favorable outcomes on preservation of renal function and histology than Ramipril alone in Col4α3 KO Alport mice. Studies are currently ongoing to investigate the underlying mechanisms of action.
Funding
- Private Foundation Support