【作者】 刘育军；

【导师】 黄文政；

【作者基本信息】 天津中医学院 ， 中医内科学， 2003， 博士

【摘要】 目的： IgA肾病是原发性肾小球疾病中最常见的病理类型之一，约有50％的患者在患病20年后进行性发展至终末期肾衰竭。随着近年来研究的深入，人们已经认识到，原发性肾小球疾病肾功能的进行性恶化同肾小管间质损害密切相关。本研究通过复制IgA肾病大鼠模型，观察肾络宁对IgA肾病大鼠肾小管间质细胞因子及细胞外基质代谢的影响，探讨该方防治IgA肾病肾小管间质损害的作用机理。 方法： 通过口服并定时尾静脉注射牛血清白蛋白后，复合葡萄球菌肠毒素感染的方法复制IgA肾病模型，同时给予肾络宁治疗，以肾炎康复片为对照组，观察血尿素氮、血肌酐、24小时尿蛋白定量、尿NAG酶活性、肾脏组织形态学、超微结构及免疫复合物沉积的情况，利用原位分子杂交和免疫组织化学的方法，结合计算机病理图象分析，观察肾络宁对IgA肾病大鼠肾组织转化生长因子β₁（TGF β-1）、Ⅲ型胶原、纤溶酶原激活物抑制剂（PAI-1）、基质金属蛋白酶（MMP-1）和组织型金属蛋白酶抑制剂（TIMP-1）基因表达的影响。 结果： （1）肾络宁组的血尿素氮、血肌酐、尿蛋白、尿NAG酶含量与模型组相比明显降低（P＜0.01）。（2）Masson染色计算机图像分析表明模型组肾小管管腔面积与肾小管面积的比值明显低于正常组（P＜0.01），肾络宁组和肾炎康复片组明显高于模型组（P＜0.01），且肾络宁组优于肾炎康复片组。（3）模型组肾间质TGFβ₁、Ⅲ型胶原、PAI-1、TIMP-1表达均较正常组增高（P＜0.01），肾络宁组与肾炎康复片组均低于模型组（P＜0.01），且肾络宁组优于肾炎康复片组（P＜0.05）。（4）模型组MMP-1表达较正常组升高（P＜0.01），肾络宁组与肾炎康复片组较模型组升高更为明显（P＜0.01或P＜0.05），且肾络宁组优于肾炎康复片组（PMO．05）。结论： （l）肾络宁能减轻IgA肾病模型大鼠的血尿素氮、血肌配、尿蛋白和尿NAG酶含量，是防治 IgA肾病及其伴发的肾小管间质病变的有效方剂。（z）肾络宁能减轻 IgA肾病模型大鼠肾小管间质病理损害。（3）肾络宁的上述作用可能与其抑制肾小管间质TGF p；、HI型胶原、PM－1、TIMp－1的表达及提高L州P－1表达有关，这可能是其防治1的肾病肾小管间质损害的机理所在。更多还原

【Abstract】 Objective:IgA nephrosis (IgAN) is one of the most common pathologic types of primary glomerular diseases, there are about 50% patients with IgAN going to the end stage renal failure. Recently, with the further studies, people realized the proceeding deterioration of renal function has intimate correlation with tubulointerstitial lesions. The aim of the following research is to investigate the effects of Shenluoning (SHLN) formula on cytokines and extracellular matrix metabolism in tubulointerstitial tissue of IgAN model rats and discuss the action mechanism of the formula preventing and curing the pathologic changes in tubulointerstitial tissue.Method:Replicating IgAN rats model by taking orally and time-controlled vein injecting bovine serum albumin (BSA) and staphylococcus enterotoxin B (SEE), giving SHLN as treatment. At the same time Shenyankangfupian (SHYKFP) act as reference group, to observe blood urine nitrogen (BUN), serum creatinine (SCr), urine β-D-N-Acetyl glucosaminidase (NAG), 24 hours urine protein quantity, kidney morphology, ultrastructure and immune complex deposition. Using in situ hybridization(ISH), immunohistochemistry and computer image analysis to observe the effects of SI’LN on the expression of transforming growth factor β1(TGFβ1), collagen type III(Col-III), plasminogen activator inhibitor-1 (PAI-1), matrix metalloproteases-1 (MMP-1) and tissue inhibitors of matrixmetalloproteases-1 (TIMP-1) in tubulointerstitial of IgAN model rats.Results:(1) The contents of BUN, SCr, 24 hours urine protein quantity and urine NAG in SHLN group remarkablely decreased comparing with that in model group (P<0. 01 )0 (2) The result of Masson stain computer image analysis indicates the area ratio value of tubular cavity and tubule of model group is lower than that of normal group (P<0. 01) , SHLN group and SHYKFP group is better than model group (P<0. 01) , moreover, SHLN group is better than SHYKFP group (P<0. 05) .(3) In interstitial, the mRNA expression of TGFβ1, Col-III, PAI-1, TIMP-1 of model group are higher than that of normal group (P<0. 01) , SHLN group and SHYKFP group is better than model group (P<0. 01) and SHLN group is better than SHYKFP group (P<0. 05) .(4) Among the four groups, the expression of MMP-lmRNA of model group is little higher than normal group (P<0. 01) , SHLN group and SHYKFP group are obviously higher than model group (P<0. 01 or P<0. 05) , moreover, SHLN group is better than SHYKFP group (P<0. 05) .Conclusions:(1) SHLN is one of the effective formula for IgAN and tubulointerstitial lesions because the formula can decrease BUN, SCr, urine protein and urine NAG of IgAN model rats. (2) SHLN can release tubulointerstitial pathologic injury of IgAN model rats. (3) The above-mentioned actions may be relative with that SHLN can down-regulate the expression of TGF β1, Col-III, PAI-1, TIMP-1 and up-regulate that of MMP-1, those may be the mechanisms of SHLN preventing and curingtubulointerstitial lesions of IgAN.更多还原