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目的探讨益肾化瘀方治疗肾间质纤维化的可能作用机制。方法将126只SD大鼠随机分为假手术组、模型组、缬沙坦组及益肾化瘀方高、中、低剂量组,每组21只。除假手术组外各组采用单侧输尿管结扎法制备肾间质纤维化模型,于造模后次日假手术组、模型组予生理盐水20 ml/(kg·d),益肾化瘀方高、中、低各剂量组分别予益肾化瘀方浓缩液32、16、8 g/(kg·d),缬沙坦组予缬沙坦胶囊溶液13.3 mg/(kg·d),每天灌胃1次,共给药28天。分别于术后第7、14、28天(每个时间点取材7只)光镜下观察肾间质病理改变并进行肾间质纤维化评分,检测大鼠肾组织中基质金属蛋白酶1(MMP-1)mRNA、基质金属蛋白酶组织抑制剂1(TIMP-1)mRNA的表达。结果光镜下HE和Masson染色显示,模型组大鼠造模7天后各组大鼠即出现肾间质水肿,间质内炎症细胞呈灶性浸润,至28天大量肾小管萎缩或消失,纤维化程度呈进展性加重。各治疗组肾间质炎细胞浸润数量减少,纤维化程度较模型组均有不同程度的减轻,益肾化瘀方高剂量组与缬沙坦组的病理改变相当。与假手术组同时间点比较,其余各组大鼠在第14、28天时肾间质纤维化评分及肾组织中MMP-1mRNA、TIMP-1mRNA表达均明显升高(P<0.05或P<0.01);与模型组同时间点比较,益肾化瘀方高、中、低剂量组和缬沙坦组大鼠在第14、28天时肾间质纤维化评分明显降低,益肾化瘀方高剂量组在第28天时MMP-1mRNA表达继续增加,而在第7、14、28天时TIMP-1mRNA表达明显降低(P<0.05或P<0.01)。结论益肾化瘀方可能通过抑制肾组织TIMP-1的表达,纠正MMP-1/TIMP-1失衡,从而显示出拮抗肾间质纤维化的作用。
Objective To investigate the possible mechanism of Yishen Huayu Recipe in treating renal interstitial fibrosis. Methods 126 SD rats were randomly divided into sham operation group, model group, valsartan group and Yishen Huayu Fang high, medium and low dose group, 21 in each group. In addition to the sham operation group, the rats in each group were given unilateral ureteral ligation to establish the model of renal interstitial fibrosis. The rats in the sham-operated group were treated with normal saline 20 ml / (kg · d), Yishen Huayu Fang High, medium and low dose groups were given Yishen Huayu Fang concentrate 32,16,8 g / (kg · d), valsartan group valsartan capsules solution 13.3 mg / (kg · d), daily Gavage 1 times a total of 28 days. The pathological changes of renal interstitium were observed under light microscope on the 7th, 14th and 28th day after operation (7 at each time point), and the renal interstitial fibrosis was evaluated. The expression of matrix metalloproteinase 1 (MMP) -1) mRNA and tissue inhibitor of metalloproteinase 1 (TIMP-1) mRNA expression. Results HE and Masson staining under light microscope showed that the rats in model group showed renal interstitial edema after 7 days of modeling. Inflammatory cells in the interstitial showed focal infiltration. A large number of renal tubules atrophied or disappeared by 28 days. Degree of progress was aggravated. The number of renal interstitial inflammatory cells in each treatment group decreased, the degree of fibrosis compared with the model group were relieved to varying degrees, Yishen Huayu Fang high-dose group and the valsartan group pathological changes. At the same time point, compared with the sham operation group, the expression of MMP-1mRNA and TIMP-1mRNA in the other groups were significantly increased on the 14th and 28th days (P <0.05 or P <0.01) ); At the same time point compared with the model group, the Yishen Huayu Fang high, middle and low dose group and the valsartan group rats on the 14th and 28th days, the renal interstitial fibrosis score was significantly reduced, The expression of MMP-1 mRNA in the dose group continued to increase on the 28th day, while the TIMP-1 mRNA expression was significantly decreased on the 7th, 14th and 28th days (P <0.05 or P <0.01). Conclusion Yishen Huayu Recipe can inhibit the expression of TIMP-1 in renal tissue and correct the imbalance of MMP-1 / TIMP-1 and thus show the antagonism of renal interstitial fibrosis.