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Abstract: SA-PO406

Liraglutide's Unveiled Renoprotective Mechanism in Type 1 Diabetes: Insights into Macrophage Polarization

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Youssef, Natalie, American University of Beirut, Beirut, Lebanon
  • Noureldein, Mohamad, American University of Beirut, Beirut, Lebanon
  • Al Moussawi, Sarah, American University of Beirut, Beirut, Lebanon
  • Eid, Assaad Antoine, American University of Beirut, Beirut, Lebanon

Group or Team Name

  • Eid's Lab.
Background

Diabetic Kidney Disease is a major complication of type 1 (T1D) and type 2 (T2D) diabetes. While the GLP-1RA liraglutide, has shown promise in protecting the kidneys of individuals with T2D, its effects T1D are not well-studied. Additionally, the underlying mechanism through which liraglutide provides renoprotection in T1D or T2D requires further investigation. Macrophages are known to contribute to the development and progression of DKD. Upon infiltrating the glomeruli, they tend to adopt a pro-inflammatory M1 phenotype rather than an anti-inflammatory M2 phenotype. In addition to inflammation, excessive production of ROS is implicated in DKD progression. This study aims to investigate the renoprotective effects of liraglutide in T1D and examine its influence on shifting macrophage polarization towards the anti-inflammatory M2 phenotype by modulating NADPH oxidase.

Methods

C57/BL6J adult male mice were divided into 3 groups (n=5/group): C group, T1D group (induced by 3 consecutive doses of STZ), and T1D group treated with liraglutide (0.3 mg/kg twice daily). After a 13-week treatment period, the mice were sacrificed, and kidneys were isolated for analysis.

Results

Our results show that liraglutide improves kidney injury in T1D mice manifested by a reduction in kidney hypertrophy, BUN, ACR, proteinuria, glomerular hypertrophy, glomerulosclerosis, as well as glomerular collagen deposition. These findings were associated with decreased expression of inflammatory cytokines, as well as the M1 macrophage specific markers. Moreover, the levels of the anti-inflammatory cytokines were increased, and this was associated by an increase in the M2 macrophage specific markers. Furthermore, liraglutide treatment attenuated ROS production manifested by decreased NADPH oxidase activity through an inhibition of NOX2 and NOX4. Of interest, liraglutide treatment was associated with activation of the NADPH oxidases DUOX isoforms, indicating a more controlled and regulated ROS production, which may be involved in redox signaling and tissue homeostasis.

Conclusion

Our data highlight an anti-inflammatory renoprotective effect of liraglutide. This is manifested by a notable shift in macrophage polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, through the modulation of NADPH oxidase activity in T1D.