Abstract: FR-PO181
SGLT2 Inhibition Attenuates ROS Production by Regulating Cytochromes P450 and Their Metabolites in Diabetic Kidney
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
- Dia, Batoul, American University of Beirut, Beirut, Lebanon
- Azar, Sami, American University of Beirut Medical Center, Beirut, Lebanon
- Eid, Assaad Antoine, American University of Beirut/Faculty of Medicine, Beirut, Lebanon
Background
Diabetic kidney disease (DKD) is currently the major common cause of end-stage renal disease worldwide. DKD is a main contributor to the increased risk of cardiovascular death in diabetes consequently increasing the global burden of diabetes-associated morbidity and mortality. Sodium–glucose cotransporter 2 (SGLT2) inhibitors, a new class of oral antihyperglycemic agents, revealed promising cardiac and renal protection in diabetic patients. However, the complete spectrum of pathways that can be affected by SGLT2 inhibition is not yet fully elucidates.
Arachidonic acid (AA) is metabolized by several cytochrome 450 (CYP) isoforms to produce 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs). CYPs of the 4A and 4F subfamilies form 20-HETE, the 2B, 2C and 2J subfamilies form EETs. Previous data from our lab show that alteration in CYPS metabolites contribute to renal damage in a diabetic milieu by altering ROS production. Moreover, CYPs have been shown to be significant sources of oxidative stress in kidneys and other organs. In this study we aim to investigate the mechanistic pathway by which SGLT2 inhibition exerts its reno-protective effect.
Methods
Dapagliflozin (SGLT2 inhibitor), HET0016 (20-HETE inhibitor), and AUDA (sEH inhibitor increasing EETs availability) were administered to Type-2 diabetic mice. Functional, histological and biochemical studies were performed.
Results
In our study, we show that diabetes-induced extracellular matrix accumulation, increases glomerular hypertrophy, induces glomerulosclerosis and albuminuria. These observations were accompanied by increased ROS production associated with alteration in CYPs 4A and 2C11 expression concomitant with alteration in 20-HETE and EETs formation. Diabetes-induced glomerular injury was blocked by HET0016, an inhibitor of CYPs 4A or by the use of AUDA, an EET activator. Of interest, SGLT2 treatment restored glomerular integrity and renal function by decreasing 20-HETE production and increasing EETs formation. Concomitantly, SGLT2 inhibition regulated the observed increase in the expression and accumulation of TGF-Beta, known to Play a major role in glomerular injury.
Conclusion
These findings suggest a new mechanistic pathway by which SGLT2 inhibitors exerts their protective effect in DKD