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Baettig, N.
The Role of A-971432, a Selective Agonist of Sphingosine 1-Phosphate Receptor 5, in the Experimental Model of Nephrotoxic Serum Nephritis
Humanmedizin; [ Diplomarbeit ] Medizinische Universität Graz; 2022. pp.


Authors Med Uni Graz:
Artinger Katharina
Eller Kathrin

Background: Current treatment regimens of rapidly progressive glomerulonephritis (RPGN) are associated with severe adverse effects. Therefore, a greater understanding and knowledge of the pathogenesis in this aggressive clinical form of glomerulonephritis (GN) is important, ultimately aiming to achieve novel targets for further effective therapy options. Sphingosine 1-phosphate (S1P) and the receptors (S1PR) have been shown to be involved in multiple forms of GN. Thus, we evaluated the influence of a selective S1P5 receptor agonist, named A-971432, in a murine model of experimental nephrotoxic serum nephritis (NTS). Methods: Three days after immunization against rabbit IgG, NTS was induced in eight to twelve weeks old male C57BL/6J mice. Starting on the same day as immunization, a daily intraperitoneal treatment with selective S1P5 receptor agonist A-971432, the nonselective S1P1 and S1P5 receptor agonist BAF-312 or vehicle was performed until day 9 after NTS induction. Results: Albuminuria in mice treated with A-971432 was comparable to mice which received BAF-312 or vehicle. Furthermore, no significant differences in humoral immune response were found. The three groups did not differ significantly in terms of their evaluated PAS-score or tubular cast formation in the kidney, although a tendency of decreased numbers of tubular casts in mice treated with A-971432 was observed. Infiltrating CD4+ cells into the kidney were increased in the BAF-312-treated mice compared to vehicle-treated (p = 0.014) as well as to the A-971432-treated mice (p = 0.014). Additionally, mice receiving BAF-312 therapy also showed a decreased number of CD8+ cells in contrast to mice with A-971432 therapy (p = 0.004). Differences of infiltrating innate immune cells into the kidney expressing CD68 and Ly6G were not detected. The CD1d-tetramer staining in spleen presented an increased number of natural killer T (NKT) cells in the BAF-312-treated mice compared to vehicle-treated (p = 0.017) and A-971432-treated mice (p = 0.014). Conclusion: Treatment of A-971432 did not improve the course of NTS compared to the vehicle group after short time treatment. BAF-312 decreases T cell infiltration into the kidney probably by S1P1 receptor, whereas NKT cells increase in the spleen.

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