Xu Min, Liu Dan, Ding Li-hong, Ma Kun-ling, Wu Min, Lv Lin-li, Wen Yi, Liu Hong, Tang Ri-ning, Liu Bi-cheng
Institute of Nephrology, Division of Nephrology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China.
Acta Pharmacol Sin. 2014 Dec;35(12):1537-45. doi: 10.1038/aps.2014.100. Epub 2014 Nov 17.
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.
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.
AO rats exhibited gradually increased urinary protein excretion accompanied by elevated urinary N-acetyl-β-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-α 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.
FTY720 alleviates tubulointerstitium inflammation in an AO rat model of nephropathy via down-regulation of the Sphk1 pathway.
FTY720是一种新型低细胞毒性免疫调节药物，目前用于治疗多发性硬化症。在本研究中，我们探究了FTY720对白蛋白过载诱导的大鼠肾病中炎性细胞浸润的影响。
雄性Wistar大鼠接受右侧肾切除术并分为3组。术后1周，白蛋白过载（AO）组用牛血清白蛋白（5 g·kg⁻¹·d⁻¹，腹腔注射）治疗9周；AO + FTY720组给予牛血清白蛋白（5 g·kg⁻¹·d⁻¹，腹腔注射）加FTY720（0.5 g·kg⁻¹·d⁻¹，腹腔注射）9周；对照组每日腹腔注射等量生理盐水。肾切除术后9周处死所有大鼠。
AO大鼠尿蛋白排泄逐渐增加，同时尿N - 乙酰 - β - O - 葡萄糖苷酶活性升高，两者均在第7周达到峰值。此外，AO显著增加循环中的淋巴细胞和单核细胞以及募集到肾小管间质的炎性细胞，以及炎性细胞因子MCP - 1、TNF - α和IL - 6的表达，以及肾脏中鞘氨醇 - 1 - 磷酸（S1P）受体S1pr1和S1pr3，和S1P合成酶鞘氨醇激酶1（Sphk1）的表达。同时给予FTY720可显著减轻所有AO诱导的病理变化。
FTY720通过下调Sphk1途径减轻AO大鼠肾病模型中的肾小管间质炎症。
