ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

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

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