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Abstract: SA-PO430

SGLT2 inhibition Alters Pdk4 and Ces1g Expression in a Mouse Model of Diabetes

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Long, Anne, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Hato, Takashi, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Zollman, Amy, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Overstreet, Jessica Marie, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Sutton, Timothy A., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Dagher, Pierre C., Indiana University School of Medicine, Indianapolis, Indiana, United States
Background

Diabetes mellitus (DM) continues to be the major contributor to the development of chronic kidney disease (CKD). SGLT2 inhibitors (SGLT2i) have emerged as an important therapeutic intervention to slow the progression of CKD in patients with and without DM. However, the mechanisms by which SGLT2i confer a protective effect in CKD have not been fully elucidated. To further explore the protective mechanisms of SGLT2i in the kidney, we utilized Riboseq to examine the translatome in a mouse model of type 2 DM following SGLT2i treatment.

Methods

8-week-old db/db (Kallis strain) and db/m (background control) mice were gavaged with 1mg/kg of dapagliflozin (dapa) or vehicle control daily for 4 weeks. Mice were subsequently euthanized and kidneys were harvested for bulk Riboseq and RNA seq.

Results

Riboseq analysis revealed that SGLT2i treatment of db/db mice significantly decreased kidney expression of pyruvate dehydrogenase kinase 4 (Pdk4). Given that Pdk4 is a known inhibitor of pyruvate dehydrogenase, this suggests SGLT2i alters glucose utilization and energy production in the kidney. Additionally, SGLT2i significantly increased the expression of Ces1g (carboxylesterase 1g) (Figure 1). Ces1g is involved in cholesterol and fatty acid utilization.

Conclusion

To our knowledge, this is the first report of SGLT2i effects on Pdk4 and Ces1g expression in the kidney. These data suggest that the protective effects of SGLT2i may include significant alterations in pathways regulating glucose and lipid metabolism. Ongoing studies will determine if direct manipulation of Pdk4 and/or Ces1g provides kidney protective effects in DM independent of SGLT2i.

Funding

  • NIDDK Support