Dapagliflozin in Addition to Ramipril Ameliorates Kidney Disease Progression in Mice with Alport Syndrome
Bibliographic record
Abstract
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
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".