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Abstract: SA-PO246

Reno-Protective Effect of Liraglutide in Type 1 Diabetes Mellitus (T1DM): Shifting Macrophage Polarization Towards the M2 Anti-Inflammatory Phenotype Through NADPH/TRP Dual Inhibition

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Youssef, Natalie, American University of Beirut, Beirut, Lebanon
  • Noureldein, Mohamad, American University of Beirut, Beirut, Lebanon
  • Ziyadeh, Fuad N., American University of Beirut, Beirut, Lebanon
  • Eid, Assaad Antoine, American University of Beirut, Beirut, Lebanon
Background

Diabetic kidney disease (DKD) is a major complication of diabetes. It is speculated that macrophages may be involved in the initiation as well as the progression of the immune response in DKD. After infiltrating the glomeruli, macrophages can polarize into an M1 pro-inflammatory phenotype or an M2 anti-inflammatory one. In addition to inflammation, extensive data from the literature highlight the deleterious effects of reactive oxygen species (ROS) over-production as well as dysregulation of calcium signaling on progression of DKD. Several hypoglycemic agents such as liraglutide, a GLP-1RA, have been investigated for their reno-protective effects. However, their exact mechanism of action still needs to be elucidated. Herein, we aim to investigate the reno-protective effect of liraglutide in type 1 diabetes mellitus (T1DM) by regulating macrophage polarization through the NADPH/TRP signaling pathway.

Methods

Functional, histopathological, biochemical and molecular parameters were assessed in control, T1DM, and T1DM C57/BL6J mice treated with liraglutide (0.3 mg/kg body weight) for 13 weeks.

Results

Liraglutide treatment improves kidney injury as assessed by improved BUN, urinary albumin to creatinine ratio (ACR), and proteinuria. This reno-protective effect of liraglutide was further confirmed using histopathology analysis exhibited by reduced glomerular hypertrophy, decreased glomerulosclerotic index and collagen deposition. Of interest, these results were associated with decreased mRNA expression of inflammatory cytokines, as wells as the M1 phenotype specific markers STAT1, CCL5, CXCL9, and CXCL10. This was paralleled by an increase in the mRNA expression of anti-inflammatory cytokines, as well as the M2 phenotype specific markers ARG-1, CD206, Retnla, CCL17 and CCL22. In addition, liraglutide treatment attenuated ROS overproduction by reducing NADPH oxidase activity by decreasing DUOX-1 and DUOX-2 levels. These observations were paralleled by a decrease in diabetes-induced TRPC6 and TRPM2 protein expression and mRNA levels.

Conclusion

To our knowledge, this is the first study to show an anti-inflammatory reno-protective effect of liraglutide in T1DM manifested by a shift in macrophage polarization towards the M2 phenotype possibly through NADPH/TRP dual inhibition.

Funding

  • Private Foundation Support