肾康注射液调控ERK1/2/MMPs信号通路促进肾衰竭模型鼠细胞外基质降解的作用和机制  

Effects and mechanisms of Shenkang injection promoting extracellular matrix degradation via regulating ERK1/2/MMPs signaling pathway in renal failure rats

作　　者：杨晶晶[1] 毛志敏[1] 万毅刚[2,3] 吴薇[1] 黄燕如 石格 韩文贝 姚建 

机构地区：[1]南京中医药大学中西医结合鼓楼临床医学院中医科,江苏南京210008 [2]南京大学医学院附属鼓楼医院中医科,江苏南京210008 [3]南京中医药大学肾病研究所,江苏南京210029 [4]Division of Molecular Signaling,Department of Advanced Biomedical Research,Interdisciplinary Graduate School of Medicine and Engineering,University of Yamanashi

出　　处：《中国中药杂志》2016年第20期3805-3813,共9页China Journal of Chinese Materia Medica

基　　金：国家自然科学基金面上项目(81374030;81573903)

摘　　要：探讨肾康注射液(Shenkang injection,SKI)在体内调控细胞外信号调节激酶(extracellular-signal regulated protein kinase,ERK)1/2/基质金属蛋白酶(matrix metalloproteinases,MMPs)信号通路而改善肾衰竭模型鼠细胞外基质(extracellular matrix,ECM)降解的作用和机制。将20只大鼠随机分为假手术组、模型组、SKI组、马来酸依那普利(enalapril maleate,EM)组。采用腺嘌呤灌胃联合单侧输尿管结扎术(unilateral ureteral obstruction,UUO)建立肾衰竭模型。造模后,SKI组和EM组大鼠分别经腹腔注射或灌胃给予SKI或EM悬浊液,其余2组大鼠经灌胃给予蒸馏水,共3周;其间,检测各组大鼠24 h尿蛋白排泄量(urinary protein excretion,Upro)和尿N-乙酰-β-D-氨基葡萄糖苷酶(urinary N-acety1-β-D-glucosaminidase,UNAG);给药3周后,处死全部大鼠,抽取血液,摘除双肾,观察肾组织形态特征,检测血清生化指标和肾组织IV型胶原(collagen type IV,CIV),MMP-2,MMP-9,金属蛋白酶组织抑制剂(tissue inhibitors of metalloproteinase,TIMP)-1,ERK1/2以及磷酸化ERK1/2(phosphorylated-ERK1/2,p-ERK1/2)蛋白表达量。结果表明,经SKI干预后,模型鼠血清肌酐(serum creatinine,Scr),血清尿素氮(blood urea nitrogen,BUN),尿酸(uric acid,UA),白蛋白(albumin,Alb),Upro,UNAG以及肾脏组织形态均得到不同程度的改善,这些作用与EM相仿;SKI还可以调节模型鼠肾组织MMP-2,MMP-9,TIMP-1蛋白表达,下调p-ERK1/2蛋白表达,这些作用不同于EM。总之,SKI在体内可能是通过调控肾组织ERK1/2信号通路活性,干预MMPs/TIMP-1表达,促进ECM降解,延缓肾衰竭进展。This study aimed to clarify preliminarily the effects and mechanisms of Shenkang injection（ SKI） promoting extracellular matrix（ ECM） degradation via regulating extracellular-signal regulated protein kinase（ ERK） 1 /2 / matrix metalloproteinases（ MMPs） signaling pathway in renal failure rats. Twenty rats were randomly divided into 4 groups： the Sham group,the Model group,the SKI group and the Enalapril maleate（ EM） group. The model rats with renal failure were induced by intragastric administration of adenine and unilateral ureteral obstruction（ UUO）. After modeling,the rats in SKI group and EM group were intervened by intraperitoneal injection of SKI or intragastric administration of the EM suspension,while the rats in Sham group and Model group were administrated with distilled water respectively for 3 weeks. The 24 h urinary protein excretion（ Upro） and urinary N-acety1-β-D-glucosaminidase（ UNAG） in all rats were tested after drug administration. All rats were sacrificed after drug administration for 3 weeks,blood and kidney were collected,renal morphological characteristics were observed. Furthermore,serum biochemical indices and the protein expressions of collagen type IV（ CIV）,MMP-2,MMP-9,tissue inhibitors of metalloproteinase（ TIMP）-1,ERK1 /2 and phosphorylated-ERK1 /2（ p-ERK1 /2） in the kidney were evaluated respectively. The results indicated that,after the intervention of SKI,serum creatinine（ Scr）,blood urea nitrogen（ BUN）,uric acid（ UA）,albumin（ Alb）,Upro,UNAG and renal morphological change in model rats were improved at different levels,respectively. Moreover,these actions were similar to EM. In addition to these,SKI adjusted the protein expressions of MMP-2,MMP-9and TIMP-1,and down-regulated the protein expressions of p-ERK1 /2 in the kidney. Moreover,these actions were different from EM.In conclusion,SKI promotes ECM degradation and delays the progression of renal failure possibly through regulating ERK1 /2 signaling pathway activation

关 键 词：肾康注射液 肾衰竭 细胞外基质 基质金属蛋白酶 细胞外信号调节激酶1/2信号通路 

分 类 号：R285.5[医药卫生—中药学] R-332[医药卫生—中医学]