The sphingosine-1-phosphate receptor agonist FTY720 prevents the development of anti-glomerular basement membrane...

The sphingosine-1-phosphate (S1P) agonist FTY720 prolongs the survival of organ allograft and attenuates autoimmune-mediated injury in experimental models. Most cases of glomerulonephritis (GN) in human appear to be immunologically initiated. In this study, we evaluated the potential therapeutic role of FTY720 in GN via a mouse anti-glomerular basement membrane (GBM) model. Mice were immunized with rabbit IgG in complete Freund's adjuvant (CFA) followed by an intravenous injection of a rabbit anti-mouse GBM serum. Disease and immune responses were assessed on day 14. Mice were treated with FTY720 (0.3 or 3 mg/kg) and prednisone (10 mg/kg) from days 0 to 14. The S1P modulator reduced proteinuria, serum creatinine, crescent formation and serum IgG level. The expressions of splenic S1P receptor and renal Th-1 cytokine were also inhibited at the transcription stage. Treatment with FTY720 increased splenocyte production of protective Th2 cytokine IL-4 and promoted the apoptosis of splenic CD4+ T cells in the animal models, which suggests that FTY720 played a protective role at the induction stage of GN by inhibiting mRNA expressions of splenic S1P receptor 1, S1P receptor 2, and S1P receptor 5.