巨噬细胞迁移抑制因子对2型糖尿病小鼠肾脏损害的影响

Effect of macrophage migration inhibitory factor on renal damage in type 2 diabetic mice

目的利用db/db、db/m小鼠研究巨噬细胞迁移抑制因子(MIF)对糖尿病肾病(DN)进展的影响。方法利用MIF抑制剂ISO-1干预db/db、db/m小鼠,观察不同分组小鼠血糖、蛋白尿、肾脏组织巨噬细胞浸润及细胞外基质沉积程度的差异,分析MIF对DN的影响。结果db/db小鼠血糖水平随时间增高,腹腔注射ISO-1(20 mg/kg,2次/周)后能降低db/db小鼠的血糖并改善糖耐量异常(P<0.05)。(1)与db/m小鼠相比,db/db小鼠的尿蛋白定量和尿蛋白肌酐比显著升高(P<0.05),ISO-1干预后,db/db小鼠两者均明显降低(P<0.05);(2)db/db小鼠肾脏中的MIF及IL-6、TNF-α表达较db/m小鼠升高(P<0.05),ISO-1干预后,IL-6、TNF-α、CD86和诱导型一氧化氮合酶均出现较明显的下调(P<0.05);(3)db/db小鼠肾小管组织中纤维黏连蛋白和Ⅰ型胶原蛋白表达较db/m小鼠上调,同时E钙粘蛋白下调,ISO-1干预后,上述指标出现相反的改变(P<0.05)。结论MIF能够影响血糖、蛋白尿、肾脏巨噬细胞浸润及细胞外基质沉积等多个环节,MIF被抑制后能延缓db/db小鼠DN损害,是潜在的DN的治疗靶点。

Objective To investigate the effects of macrophage migration inhibitory factor(MIF)on diabetic nephropathy(DN)in the db/db and db/m mice.Methods ISO-1(MIF inhibitor),was used to intervene db/db mice.The levels of blood glucose,proteinuria,macrophage infiltration and extracellular matrix deposition were detected and compared in different groups.Results db/db mice showed time-dependent increase of blood glucose.Intraperitoneal injection of ISO-1(20 mg/kg,2 times per week)can reduce the blood glucose level and improve the abnormal glucose tolerance.Compared with db/m mice,the urinary protein quantitation and urinary protein creatinine ratio of db/db mice were significantly increased,but gradually reduced after ISO-1 intervention.Compared with db/m mice,the levels of MIF,interleukin 6(IL-6)and tumor necrosis factor-α(TNF-α)in the kidney of db/db mice were significantly higher,and the levels of IL-6 and TNF-αwere down-regulated after the intervention of ISO-1.After ISO-1 intervention,the levels of CD86 and inductible nitric oxide synthase were significantly down-regulated in the kidney of the db/db mice;ISO-1 could reduce the expression of fibronectin and type I collagen,and promote the expression of E-cadherin.Conclusions MIF can affect blood glucose,proteinuria,macrophagic infiltration and extracellular matrix deposition in db/db mice.The inhibition of MIF could delay the progression of DN in db/db mice,so MIF may be a potential target for the treatment of DN.