FTY720 inhibits tubulointerstitial inflammation in albumin overload-induced nephropathy of rats via the Sphk1 pathway

Aim: FTY720, a new immunomodulatory drug with low cytotoxicity, is currently used to treat multiple sclerosis. In this study, we investigated the effects of FTY720 on inflammatory cell infiltration in albumin overload-induced nephropathy of rats. Methods: Male Wistar rats were subjected to right-side nephrectomy and divided into 3 groups. One week after the surgery, albumin overload (AO) group was treated with BSA (5 g.kg(-1).d(-1),ip) for 9 weeks; AO+FTY720 group was given BSA (5 g.kg(-1).d(-1), ip) plus FTY720 (0.5 g.kg(-1).d(-1), ip) for 9 weeks; and control group received daily ip injection of equivalent volume of saline. All rats were killed 9 weeks after nephrectomy. Results: AO rats exhibited gradually increased urinary protein excretion accompanied by elevated urinary N-acetyl-beta-O-glucosaminidase activity, and both reached their peak values at week 7. Furthermore, AO significantly increased lymphocytes and monocytes in circulation and the inflammatory cells recruited to tubulointerstitium, and the expression of inflammatory cytokines MCP-1, TNF-alpha and IL-6, as well as sphingosine 1-phosphate (S1P) receptors S1pr1 and S1pr3, and S1P-synthesizing enzyme sphingosine kinase 1 (Sphk1) in the kidney. Concomitant administration of FTY720 significantly attenuated all the AO-induced pathological changes. Conclusion: FTY720 alleviates tubulointerstitium inflammation in an AO rat model of nephropathy via down-regulation of the Sphk1 pathway.