糖皮质激素抑制狼疮肾炎MMP-2与MMP-9表达的实验研究

Experimental study of the inhibitory effects of methylprednisolone on the expressions and activities of matirx metalloproteinase-2 and-9 in lupus mice

目的明确糖皮质激素调控MMP-2、MMP-9表达与活性变化与治疗狼疮肾炎的关系。方法采用MRL/lpr自发性狼疮小鼠为模型,将8wk龄小鼠随机分为甲基强的松龙(MPS)治疗组与对照组(control),MPS治疗组腹腔注射甲基强的松龙25mg·kg-1·d-1,将小鼠饲养至28wk,观察小鼠的存活率、蛋白尿、肾功能与肾脏病理改变。采用免疫组化检测MMP-2与MMP-9的表达变化,利用含有放射自显影的成像乳胶对冰冻肾组织切片进行原位明胶酶活性的检测。结果MPS能够延长狼疮小鼠的存活率(P<0·05)、降低蛋白尿的发生率(P<0·01)、降低血清尿素氮(P<0·01),并减轻肾小球、肾小管-间质以及肾小血管的病理改变(P<0·05)。狼疮小鼠肾小球内MMP-2、MMP-9的表达与活性随增龄明显增加(P<0·01)。MPS能够明显抑制肾小球MMP-2、MMP-9的表达及肾组织原位明胶酶的活性变化(P<0·01)。结论甲基强的松龙对自发性狼疮小鼠的治疗作用与抑制肾脏异常MMP-2与MMP-9的表达与活性密切相关,该作用可能是糖皮质激素治疗狼疮肾炎的机制之一。

Aim To investigate the effects of methylprednisolone(MPS) on the expressions and activities of matirx metalloproteinase-2 and-9 in lupus mice.Methods Eight-week-old MRL/lpr mice were randomly divided into MPS-treated group and control group.After administration of MPS(25 mg·kg-1·d-1,ip) for 20 weeks,survival rate,incidence of proteinuria,renal function and renal pathological changes of MPS-treated group were investigated compared to control group.Expressions of MMP-2 and MMP-9 were measured with computer image analysis of immunohistochemistry staining sections.In situ zymography was used to determine the gelatinase activities of frozen kidney sections of lupus mice.Results MPS treatment significantly decreased the amount of proteinuria(P<0.01),prolonged survival rate(P<0.05),decreased serum BUN level(P<0.01) and reduced the histological severity of glomerulonephritis(P<0.05).Immunohistochemical staining showed that both MMP-2 and MMP-9 were obviously up-regulated within glomeruli in 28-week-old mice.In situ zymography showed markedly increased gelatinase activities in kidney tissue.Both expressions and activities of MMP-2 and MMP-9 were significantly decreased after MPS administration(P<0.01).Conclusion The beneficial effects of MPS on mice lupus nephritis may be partly attributed to its inhibition of MMPs production,which is probably an additional,as yet undefined mode of actions for MPS.