芬戈莫德对血管紧张素Ⅱ介导的慢性肾脏病的影响

    Effect of FTY720 on Angiotensin Ⅱ-mediated chronic kidney diseases

    • 摘要: 目的 通过建立血管紧张素Ⅱ(Angiotensin Ⅱ,Ang Ⅱ)灌注的大鼠肾损害模型,使用药物芬戈莫德(Fingolimod,FTY720)进行干预,来评估该药物对大鼠肾功能的影响,并探讨FTY720对Ang Ⅱ灌注大鼠肾脏炎症改变的作用及可能涉及的机制,从而为肾脏疾病的治疗提供新的策略。方法 36只SPF级雄性SD大鼠随机分为3组:(1)模型组12只,即Ang Ⅱ灌注组,皮下植入含Ang Ⅱ的渗透性微量泵,持续灌注28 d(Ang Ⅱ:400 ng·kg-1·min-1);(2)干预组12只,即Ang Ⅱ+FTY720干预组,在模型组的基础上,FTY720以0.5 g·kg-1·d-1灌胃28 d;(3)对照组12只,以等量的生理盐水灌胃28 d。每周称体质量,留24 h尿液,并于第28天处死各组大鼠,经心脏采血,并留取肾脏标本。放射免疫法检测各组大鼠血液中Ang Ⅱ及肾匀浆组织中Ang Ⅱ的浓度。对尿液及血液样本进行尿蛋白与血生化分析。光镜下观察各组大鼠肾组织病理学改变并行Jablonski评分。免疫印迹法检测炎症因子TNF-α、IL-6在肾脏中的表达。结果 (1)Ang Ⅱ可导致模型组大鼠血肌酐、尿素氮水平升高,尿蛋白排泄明显增加,炎症因子TNF-α、IL-6在肾脏组织中的表达水平升高;(2)干预组的肾脏病理损伤较模型组减轻,且Jablonski评分明显低于模型组,血肌酐、尿素氮水平明显降低,尿蛋白明显减少,肾脏组织中炎症因子TNF-α、IL-6水平明显降低,差异具有统计学意义(P<0.05)。结论 FTY720可减轻Ang Ⅱ诱导的大鼠肾脏的病理损伤,可能是通过减少炎症因子的表达发挥了减轻尿蛋白,改善肾功能的作用。

       

      Abstract: Objective To assess effect of fingolimod (FTY720) on functions of the kidney in rats by establishing the rat mode of angiotensin Ⅱ (Ang Ⅱ)-perfused renal injury and using the drug to intervene the rat model; and to explore action of FTY720 on renal inflammation changes and its potentially involved mechanism in the angiotensin Ⅱ-perfused rat, so as to provide a new strategy for treatment of kidney diseases. Methods Thirty-six male SPF grade Sprague-Dawley rats were randomly divided into 3 groups:(1) model group, 12 rats, i.e. Ang Ⅱ-perfused group:, Ang Ⅱ -containing osmotic micro-pump implanted subcutaneously for 28 days (Ang Ⅱ:400 ng·kg-1·min-1); (2) intervention group, 12 rats, i.e. Ang Ⅱ+FTY720 intervention group,:intragastrical administered with FTY720 at a concentration of 0.5 g·kg-1·d-1 for 28 days on the basis of the Ang Ⅱ-perfused group; (3)Control group:12 rats, intragastrical administered with the same amount of normal saline for 28 days. Twenty four hours urine samples were preserved, blood samples were collected and kidney specimens were excised and preserved on day 28 when the rats were sacrificed. Concentrations of Ang Ⅱ in blood samples and homogenized renal tissue homogenates from the rats in various groups were detected by radioimmunoassay. Urine proteins and blood biochemical parameters were tested. Renal pathological changes in rats from various groups were observed under an optical microscope and scored by Jablonski grade. The expression levels of TNF-α and IL-6 in kidney tissue were analyzed by western blot. Results (1) Ang Ⅱ increased the levels of serum creatinine and urea nitrogen in the rats from the model group. Meanwhile, in the model group, urine protein excretion increased significantly, and expression levels of inflammatory factors of TNF-α and IL-6 in the kidney tissues were elevated. (2) Compared with the model group, the renal pathological injury was significantly alleviated in the intervention group. Meanwhile, the Jablonski grades in the intervention group were significantly lower than those in the model group. Serum creatinine and urea nitrogen levels in the intervention group were significantly reduced, and urine proteins decreased notably. The levels of inflammatory factors of TNF-α and IL-6 in the kidney tissues in the intervention group were also significantly decreased, compared to model group, with statistically significant difference(P<0.05). Conclusions FTY720 can alleviate pathological damage of the kidney in rats induced by Ang Ⅱ, which may decrease urinary proteins and improve the renal function by reducing expression of inflammatory factors.

       

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