Abstract: FR-PO281
Liraglutide-Mediated Renoprotection in Type 1 Diabetes: Modulating M1/M2 Macrophage Balance via NOX/TRP Cross-Talk
Session Information
- Diabetic Kidney Disease: Basic - 1
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
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
- Almoussawi, Sarah, American University of Beirut, Beirut, Lebanon
- Kaddoura, Tala Radwan, American University of Beirut, Beirut, Lebanon
- Ziyadeh, Fuad N., 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 (DKD) poses a substantial health burden for patients with diabetes. While studies have demonstrated the renoprotective effects of the GLP-1RA liraglutide in type 2 diabetes (T2D), its impact in type 1 diabetes (T1D) remains less explored. Although some studies suggest renoprotection in T1D, the underlying mechanism remains elusive across both T1D and T2D. Recent evidence highlights the role of macrophages in the initiation and progression of DKD, where macrophages tend to polarize to an M1 pro-inflammatory instead of an M2 anti-inflammatory phenotype. Besides, extensive data showed that ROS overproduction and calcium signaling dysregulation play a crucial role in DKD progression. Therefore, this study investigates the reno-protective mechanism of liraglutide in T1D and elucidates its effect on restoring macrophage polarization balance by modulating NOX-TRP crosstalk.
Methods
C57/BL6J mice were divided into 3 groups: control group, STZ-induced insulin deficient model mimicking T1D, and a T1D group treated with 0.3mg/kg s.c. injections of liraglutide twice daily. After 13 weeks of treatment, the kidneys were isolated for analysis.
Results
Despite hyperglycemia, liraglutide treatment significantly reduced kidney hypertrophy and improved renal function. Histopathological data confirmed reduced glomerular hypertrophy, glomerulosclerotic index, and collagen deposition. Additionally, fibronectin, Col4, WT1, nephrin, and podocin levels normalized. While liraglutide didn’t decrease macrophage infiltration, it did reduce inflammatory cytokine expression and specific M1 macrophage markers. Conversely, anti-inflammatory cytokines increased, along with markers of M2 macrophages. Liraglutide also attenuated ROS overproduction by reducing NADPH oxidase activity. However, further analysis revealed differential modulation of the different NOX isoforms. This finding underscores the pivotal role played by NOX in kidney function and macrophage responses. Besides, liraglutide restored normal TRPM2 and TRPC6 expression and increased TRPM7 expression.
Conclusion
This is the first study to show a reno-protective effect of liraglutide in T1DM manifested by a shift in macrophage polarization from M1 inflammatory to M2 anti-inflammatory phenotype by modulating NOX-TRP crosstalk.