Abstract: FR-PO191
GSK3-α/β Inhibition Attenuates Progression of CKD in Lepr-/- Mice with Type 2 Diabetes (T2D) Beyond Standard-of-Care Therapy (SOC) with Metformin/Ramipril/Empagliflozin
Session Information
- Diabetic Kidney Disease: Basic - II
November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Manga, Motrapu, Klinikum der Universität München, München, Germany
- Anguiano-Gomez, Lidia, Klinikum der Universität München, München, Germany
- Angelotti, Maria Lucia, Excellence Center for Research, Transfer and High Education Denothe, University of Florence, Florence, Italy
- Romagnani, Paola, University of Florence, Firenze, Italy
- Anders, Hans J., Klinikum der Universität München, München, Germany
Background
Dual RAS/SGLT2 inhibition significantly reduces cardiovascular, renal morbidity in patients with T2D but further retarding progression of CKD remains a global unmet medical need. GSK3α/β inhibitor BIO (6-bromo-indirubin-3’-oxime) was shown to promote podocyte differentiation in vitro, to limit Adriamycin-induced podocyte loss in vivo, hence we hypothesized that BIO’s specific mechanism-of-action would have therapeutic effects beyond SOC therapy on diabetic kidney disease (DKD)
Methods
Male BKS-Lepr-/- mice with obesity-related T2D their respective non-diabetic BKS-Lepr+/+ controls underwent uninephrectomy (1K) at 6 weeks of age to mimic CKD G2, accelerated progression of DKD. From week 12-16, all 1K mice were put to SOC therapy (1500mg/kg metformin, 6mg/kg ramipril, 480mg/kg empagliflozin) and randomized to either additional BIO (2µmol/kg) or vehicle therapy. Lepr-/- mice without proteinuria at week 12 were excluded from the study. N=10-11 per group. GFR, albuminuria, Blood glucose were monitored at regular intervals. Glomerular tuft area, density of WT-1+ podocytes and glomerulosclerosis were quantified in cortical and juxtamedullary glomeruli. Density of tertiary podocyte foot processes was analyzed as a marker of terminal podocyte differentiation by STED microscopy
Results
Primary endpoint: Lepr-/- mice, GFR increased after uninephrectomy with a progressive decrease later (A). SOC+BIO significantly attenuated GFR loss during treatment interval compared to SOC therapy alone (B).Secondary endpoints: In Lepr-/- mice, albuminuria was significantly attenuated bySOC therapy (C). SOC+BIO therapy significantly increased podocyte densityin juxtamedullary glomeruli (D). BIO showed significantly better preservation of tertiary podocyte foot processes (E)
Conclusion
GSK3-α/β inhibitor BIO has renoprotective effects beyond SOC therapy in a clinically meaningful model of progressive DKD. Optimizing animal models of DKD to better mimic the study population, co-medication, study endpoints used in clinical trials may improve the notoriously poor predictive value of animal models of DKD