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, Arianne van Koppen Search for other works by this author on: Oxford Academic Simon Hinke Janssen Pharmaceuticals , Boston , United States of America Search for other works by this author on: Oxford Academic Tri Nguyen University Medical Centre Utrecht , Utrecht, Netherlands Search for other works by this author on: Oxford Academic Amélie Dendooven Universitair Ziekenhuis Gent , Gent , Belgium Search for other works by this author on: Oxford Academic Tzu-Ling Tseng BioPreventive Medicine , Zhu-Bei , Taiwan, R.O.C. Search for other works by this author on: Oxford Academic Wei-Chan Hsu BioPreventive Medicine , Zhu-Bei , Taiwan, R.O.C. Search for other works by this author on: Oxford Academic Ingeborg Bajema University Medical Centre Groningen , Groningen , Netherlands Search for other works by this author on: Oxford Academic Aswin Menke TNO , Netherlands Search for other works by this author on: Oxford Academic Harry van Goor University Medical Centre Groningen , Groningen , Netherlands Search for other works by this author on: Oxford Academic Reinout Stoop TNO, The Netherlands Organization of Applied Science , Leiden , Netherlands Search for other works by this author on: Oxford Academic
Nephrology Dialysis Transplantation, Volume 39, Issue Supplement_1, May 2024, gfae069-1048-1206, https://doi.org/10.1093/ndt/gfae069.1048
Published:
23 May 2024
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Arianne van Koppen, Simon Hinke, Tri Nguyen, Amélie Dendooven, Tzu-Ling Tseng, Wei-Chan Hsu, Ingeborg Bajema, Aswin Menke, Harry van Goor, Reinout Stoop, #1206 Combination therapy with Lisinopril and Dapagliflozin rescues GFR decline and glomerular damage in the KKAy mouse model of diabetic kidney disease, Nephrology Dialysis Transplantation, Volume 39, Issue Supplement_1, May 2024, gfae069–1048–1206, https://doi.org/10.1093/ndt/gfae069.1048
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Abstract
Background and Aims
Male KKAy mice develop diabetic kidney disease (DKD) with progressive decline of GFR upon high fat diet feeding which is accelerated by the vasoconstrictor LNNA. In this study, efficacy of combination therapy with clinical relevant therapeutics in the form of an ACE-inhibitor (Lisinopril) and SGLT2-inhibitor (Dapagliflozin) on renal function and histopathology was investigated.
Method
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 in drinking water) and at week 8 Dapagliflozin (5 and 20 mg/kg/day in diet) 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 renal histology was scored by a team of renal histopathologists. 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 (p<0.05 vs UNX+HFD+LNNA). Pathology showed that the percentage of healthy glomeruli increased from 14% to 26% after combination therapy (Dapa 5). Interstitial fibrosis and tubular atrophy were significantly reduced by combination therapy (p<0.05 vs UNX+HFD+LNNA).
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 and interstitial fibrosis and tubular atrophy This indicates the clinical relevance of the model which can be used to study compound efficacy in both early and more advanced stages of DKD.
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© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.
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Topic:
- angiotensin-converting enzyme inhibitors
- lisinopril
- vasoconstrictor agents
- diabetic nephropathy
- renal function
- kidney failure, chronic
- diet
- drug clearance
- glomerular filtration rate
- atrophy
- combined modality therapy
- fluorescein-5-isothiocyanate
- food
- kidney glomerulus
- blood glucose
- water drinking
- histology
- kidney
- mice
- pathology
- histopathology tests
- dapagliflozin
- albuminuria
- sodium-glucose transporter 2 inhibitors
- interstitial fibrosis
- potable water
- diet, high-fat
- clinical relevance
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