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Moschovaki Filippidou, F.
The Effect of Glucagon Like Peptide-1 Receptor Agonism in T Cell Mediated Diseases: A Thorough Study of the Case of Nephrotoxic Serum Nephritis
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2019. pp.113 [OPEN ACCESS]


Authors Med Uni Graz:
Eller Kathrin
Heinemann Akos
Pieber Thomas

Background: Recent randomized controlled trials have shown that glucagon like peptide (GLP)-1 analogues like liraglutide can improve kidney function in patients with type 2 diabetes mellitus. Though the mechanism of action of this effect is not yet clear, a possibility is the anti-inflammatory potential of GLP-1 receptor (Glp1r) agonism. Thus, we aimed to test the anti-inflammatory capacity of Glp1r agonism in a non-diabetic, T cell mediated murine model of nephrotoxic serum nephritis (NTS). Methods: NTS was induced in Glp1r-/- mice and littermate controls. Furthermore, liraglutide treatment in NTS was tested in C57BL/6J mice. In vitro, murine T cells were stimulated in the presence of liraglutide or vehicle. Results: Glp1r-/- mice displayed increased renal infiltration of neutrophils and T cells after induction of NTS as compared to littermate controls. In parallel, splenocyte proliferation and Th1 cytokine transcription were increased in spleen and lymph nodes of Glp1r-/- mice after NTS induction. Nevertheless, no difference in renal outcomes such as albuminuria and histological changes was detected between the two groups. In contrast, liraglutide treatment significantly improved the renal outcome of NTS in C57BL/6 mice as reflected by decreased albuminuria and histological changes. This was accompanied by a significant decrease in the renal infiltration of T cells and macrophages and a decrease in renal Th1 cytokine transcription. Renal beneficial effects of liraglutide were mediated via the Glp1r since liraglutide failed to protect Glp1r-/- mice from NTS. In vitro, T cells stimulated in the presence of liraglutide showed decreased proliferation and IL-6 production as compared to vehicle. In addition, liraglutide blocked glycolysis and decreased the expression of Glut1 mRNA in T cells. Conclusion: Our data support the hypothesis that Glp1r agonism has anti-inflammatory potential thereby protecting mice from a T cell dependent glomerulonephritis model, possibly by inhibiting T cell proliferation and interacting with their metabolic program. Thus, Glp1r agonism by liraglutide might also be an attractive new therapeutic tool in the treatment of other T cell mediated diseases.

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