Abstract: SA-PO128
Empagliflozin Ameliorates Diabetic Nephropathy in BTBR ob/ob Mice
Session Information
- Diabetic Kidney Disease: Basic - III
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Hudkins, Kelly L., University of Washington, Seattle, Washington, United States
- Li, Xianwu, University of Washington, Seattle, Washington, United States
- Alpers, Charles E., University of Washington, Seattle, Washington, United States
Group or Team Name
- Alpers Lab
Background
The SGLT2 inhibitor empagliflozin has demonstrated success in regulating elevated blood sugars in diabetic patients via enhanced glucose excretion in the urine, and has been successful in ameliorating complications of type II diabetes including cardiovascular disease and nephropathy. We sought to test whether treatment with empagliflozin (EMPA) with and without concurrent losartan (LOS) treatment would ameliorate pathology, proteinuria and restore podocyte number in the BTBR ob/ob model of diabetic nephropathy. The latter may be a relevant mechanism that contributes to the observed benefits seen in type II diabetic patients treated with this drug.
Methods
At 18 weeks of age BTBR ob/ob and BTBR WT female mice (n=12 each group), proven to be diabetic by elevated blood glucose levels, were fed chow formulated with 300 mg/kg EMPA with and without concurrent LOS treatment (EMPA/LOS), normal chow or were given leptin (LEP) vis osmotic minipump. They were treated for 6 weeks. At the end of the experiment, at 24 weeks of age, the mice were placed into a metabolic chamber for 6 hours to obtain a timed urine and a fasting blood glucose level was recorded. The mice were then euthanized, blood collected via cardiac puncture and organs harvested for study.
Results
Treatment with LEP, EMPA and EMPA/LOS all resulted in a significant reduction of blood glucose. Only treatment with LEP resulted in weight loss. EMPA and EMPA/LOS treatment did not affect proteinuria in individual BTBR ob/ob mice while LEP replacement resulted in a significant drop in proteinuria in individual BTBR ob/ob mice. Group averages of albumin creatinine ratios (ACR) and albumin excretion extrapolated to 24 hour urines did drop significantly in all treatment groups. Additionally, all treatment arms resulted in a significant reduction of mesangial matrix accumulation and prevented glomerular hypertrophy. Analysis of podocyte number is pending.
Conclusion
From these studies, we conclude that EMPA and EMPA/LOS is nearly as effective as LEP replacement in ameliorating some of the pathology and clinical manifestations of diabetic nephropathy in the leptin deficient BTBR ob/ob mouse. Further analysis will be done to determine whether podocyte number is restored by these treatments, which may be a contributing factor to the improvement seen in human diabetic patients being treated with SGLT2 inhibitors.
Funding
- Commercial Support – Boehringer Ingelheim and Lilly IIS Grant Program for Diabetes