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Kidney Week

Abstract: FR-PO189

Reno-Protective Effect of GLP-1 Receptor Agonists: Silencing the Cross-Talk Between TRPC6 and NADPH Oxidases

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Youssef, Natalie, American University of Beirut, Beirut, Lebanon
  • Fares, Nassim, Saint Joseph University of Beirut, Beirut, Lebanon
  • Eid, Assaad Antoine, American University of Beirut/Faculty of Medicine, Beirut, Lebanon
Background

Diabetic kidney disease (DKD) is a life-threatening complication of Diabetes. DKD is characterized by podocyte injury which compromises the glomerular filtration barrier leading to proteinuria. Podocyte injury is thought to be mediated by reactive oxygen species (ROS) production via NADPH oxidases. DUOX 1 & 2 are NADPH oxidases that acquire in their structure a calcium binding site. Calcium signaling through TRPC channels is essential in podocyte function and disruption of its homeostasis leads to cytoskeleton disorganization, foot process effacement and disruption of slit diaphragm. Besides, hypoglycemic treatments such as GLP-1 receptor agonists (GLP-1RA) have been shown to exert a reno-protective effect, yet this mechanism is still not well elucidated. Herein, we aim to investigate the role of TRPC-6 channel and NADPH oxidases in kidney injury and the effect of GLP-1RA on reversing this process.

Methods

Sprague Dawley rats were allocated into five groups: control, STZ induced type I diabetic group, STZ induced type 1 diabetic group treated with Metformin or GLP-1RA or combination for a duration of 8 weeks. Functional, histopathological, biochemical and molecular studies were performed on kidney tissues from all groups.

Results

GLP-1RA treatment ameliorates kidney injury. This was transduced by a reduction in BUN, SCr, proteinuria, collagen deposition and fibrosis. Kidney tissues showed downregulation of collagen IV & fibronectin mRNA expression versus an upregulation of nephrin mRNA expression upon treatment. In addition, we noticed decreased ROS production, NADPH oxidases activity and mRNA expression of DUOXs. Moreover, reduced expression of TRPC6 but not TRPC3 was noticed upon treating with GLP-1RA. GLP-1R and AMPK expression were assessed too.

Conclusion

GLP-1RA seems to retard diabetic nephropathy by modulating the cross-talk between TRPC6 and NADPH oxidases. These clues could pinpoint novel molecular mechanisms in DKD.

Funding

  • Other U.S. Government Support