羟苯磺酸钙对糖尿病大鼠肾小球中基质金属蛋白酶-2/组织金属蛋白酶抑制物-2及Ⅳ型胶原表达的影响

Effects of Calcium Dobesilate on MMP-2、TIMP-2 and Col-Ⅳ of Diabetic Rats

目的观察羟苯磺酸钙对糖尿病大鼠肾小球基质金属蛋白酶-2/组织金属蛋白酶抑制剂-2以及Ⅳ型胶原表达的影响。方法采用单肾切除及单次腹腔注射1%STZ(65mg/kg体重)制作大鼠DM模型,大鼠经羟苯磺酸钙或蒸馏水灌胃12周后,观察各组大鼠肾脏超微结构的改变以及BG、Upro、Cc、BUN和肾重/体重的变化;免疫组化检查肾小球基质金属蛋白酶/组织金属蛋白酶抑制剂以及Ⅳ型胶原表达的变化。结果12周时,糖尿病模型(DM)组与单肾切除对照组(NC)组相比,肾重/体重、BG、BUN、Cc及Upro显著增高(P<0.05),羟苯磺酸钙治疗组(DD组)与DM组相比,除Cc变化不明显外,肾重/体重、BG、BUN及Upro均不同程度降低;电镜显示NC组大鼠肾小球细胞外基质与系膜细胞分布正常,毛细血管腔开放;DM组肾小球系膜区基质增多及系膜细胞增生,同时毛细血管部分塌陷,肾小囊部分粘连;DD组上述病理改变均有不同程度的减轻;肾脏免疫组织化学显示DD组MMP-2、TIMP-2和Col-Ⅳ明显低于DM组,但DD和DM组MMP-2、TIMP-2和Col-Ⅳ均显著高于NC组。结论羟苯磺酸钙能改善糖尿病大鼠肾功能,通过抑制Col-Ⅳ的过度积聚来改善糖尿病微血管病变,并且可能与抑制糖尿病大鼠肾脏TIMP-2表达有关。

[Objective]To observe the Effects of Calcium Dobesilate on MMP-2,TIMP-2 and Col-Ⅳ of Diabetic Rats. [Methods]Rats were induced to Diabetic model by unilateral nephrectomy and intraperitoneal injection 1% STZ（55mg/kg）, each group administrated Calcium dobesilate or distilled water respectively. Twelve weeks later, the change of the ultrastructure of kidneys and change of BG,Upro,Cc ,BUN and Kidney/body weight rate were observed in each group. Immunohistochemistry Staining was used to study the expression of MMP-2, TIMP-2 and collagen Ⅳ. [Results]After 12 weeks, BG,Upro, Cc , BUN and Kidney/body weight rate in Group DM rats increased and obviously higher than those of Group NC, but decreased statistically compared to those of Group DD. Electron microscope showed that thickness of glomerular basement membrane and mesangial cells were normal, capillary lumen was open in Group NC, but mesangial proliferation ;and matrix increase, capillary partial collapse and renal capsules partial adhesion were observed in group DM. Above pathological changes were reduced in Group DD. Immunohistochemistry Staining of glomerulus showed that expression of MMP-2,TIMP-2 and Col-Ⅳ of Group DD were obviously less than those of Group DM. [Conclusion] Calcium dobesilate can statistically improve renal function of Diabetic Rats and microangiopathy of diabetes mellitus by inhibiting the over-accumulation of collagen Ⅳ. It may also contribute to diabetes by inhibiting expression of TIMP-2.