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Abstract: PO0648

A Novel Anti-Inflammatory Renoprotective Effect of GLP-1 Receptor Agonists in Type 1 Diabetes: Shifting Macrophage Polarization

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Youssef, Natalie, American University of Beirut Faculty of Medicine, Beirut, Lebanon
  • Ghadieh, Hilda E., American University of Beirut Faculty of Medicine, Beirut, Lebanon
  • Njeim, Rachel, American University of Beirut Faculty of Medicine, Beirut, Lebanon
  • Azar, Sami, American University of Beirut Medical Center, Beirut, Lebanon
  • Ziyadeh, Fuad N., American University of Beirut Medical Center, Beirut, Lebanon
  • Fares, Nassim, Universite Saint-Joseph, Beirut, Lebanon
  • Eid, Assaad Antoine, American University of Beirut Faculty of Medicine, Beirut, Lebanon
Background

Diabetic kidney disease (DKD) is a serious complication of diabetes. Increased evidence has shown a vital role of the immune system in the pathogenesis of DKD. Macrophages infiltrate the glomeruli and can polarize into an M1 pro-inflammatory phenotype versus an M2 anti-inflammatory one. Moreover, studies from our group and others highlighted the role of NADPH oxidases induced ROS production in the progression of DKD. Several hypoglycemic agents were investigated for their reno-protective effects. Among these agents, Liraglutide, a GLP-1 receptor agonist. However, its role in modulating DKD development still needs to be elucidated, especially in type 1 diabetes mellitus (T1DM). In this study, we aim to investigate the reno-protective effect of Liraglutide in regulating the NADPH oxidases family of enzymes which are well known for their role in ROS production. More importantly we will assess the involvement of Liraglutide with macrophage polarization, a major component of the immune system.

Methods

C57/BL6J adult male mice were allocated into 3 groups: control, STZ induced T1DM, STZ induced T1DM group treated with liraglutide (0.3mg/kg, SC twice daily) for a duration of 13 weeks. Functional, histopathological, biochemical and molecular studies were performed on kidney tissues for all groups.

Results

Liraglutide treatment improves kidney injury as assessed by blood urea nitrogen, serum creatinine levels, and more importantly proteinuria. The reno-protective effect of liraglutide was further validated via histopathological findings; increased M2 macrophage infiltration, reduced collagen deposition and extracellular matrix expansion. Of interest, these results were associated with decreased mRNA expression of M1 inflammatory markers and increased mRNA expression of the M2 anti-inflammatory ones. In addition, liraglutide treatment attenuated ROS overproduction by reducing NADPH oxidase enzymatic activity paralleled by a decrease in DUOX-1 and DUOX-2 isoforms protein expression and mRNA levels.

Conclusion

To the best of our knowledge, this is the first study to show a reno-protective effect of liraglutide in DKD through shifting macrophage polarization towards the M2 anti-inflammatory phenotype possibly via inhibiting NADPH oxidases induced ROS production.

Funding

  • Private Foundation Support