Meng Liqiang, Liao Aineng, Qu Lei, Tang Jiawei, Li Xiaomei
First Hospital of Peking University, Peking University, Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Beijing 100034, China.
Zhongguo Zhong Yao Za Zhi. 2012 Jan;37(1):79-84.
OBJECTIVE: The imbalance between extracellular matrix (ECM) synthesis and degradation induces the excessive ECM deposition and thus renal fibrosis. The decoction (A&A) which is a combination of two Chinese herbs, Astragalus membranaceus var. mongholicus and Angelica sinensis, has been shown to alleviate ECM production in animal models of chronic kidney diseases. In this paper, the effect of A&A on ECM degradation was investigated with interstitial fibrosis in rats. METHOD: Male Wistar rats were randomly divided into sham, unilateral ureteral obstruction (UUO) and UAA (UUO plus A&A administration) groups. After administration of A&A (14 g x kg(-1) x d(-1)) by gavage for 3, 7 and 10 days, morphological changes were evaluated by HE, PAS and Sirius red staining technique. The expression of plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (t-PA), the activity of PAI-1 and t-PA were determined by ELISA. The activity of matrix metalloproteinases (MMP-9, MMP-2), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) were evaluated by gelatin zymography or reverse gelatin zymography, respectively. RESULT: Morphological analysis showed severe interstitial mononuclear cells infiltration, tubular atrophy, renal fibrosis and collagen expression in kidneys of UUO group, which was reduced by A&A administration (P < 0.05, UAA vs UUO group). Compared with the sham group, the expression of PAI-1 was significantly increased in UUO group by 63%, 91% and 112% at day 3, 7 and 10 respectively; and there were a remarkable decrease in UAA group by 44%, 43% and 52% at day 3, 7 and 10. The expression of active PAI-1 was strikingly increased in UUO group at day 3 [(30.5 +/- 23.8) ng x g(-1) vs. (0.0 +/- 0.0) ng x g(-1), P < 0.05)], day 7 [(36.5 +/- 11.2) ng x g(-1) vs. (0.0 +/- 0.0) ng x g(-1), P < 0.05)], and day 10 [(54.5 +/- 14.2) ng x g(-1) vs. (0.5 +/- 0.5) ng x g(-1), P < 0.05)]. The active PAI-1 was decreased in UAA group at day 7 [(14.9 +/- 0.5) ng x g(-1) vs. (36.5 +/- 11.2) ng x g(-1), P < 0.05] and day 10 [(15.4 +/- 4.8) ng x g(-1) vs. (54.5 +/- 14.2) ng x g(-1), P < 0.05]. The expression of t-PA was increased in UUO group only at day 3 [(58.1 +/- 16.5) microg x g(-1) vs. (30.1 +/- 17.3) microg x g(-1)], P < 0.05), meanwhile decreased in UAA group [(26.3 +/- 8.7) microg x g(-1) vs. (58.1 +/- 16.5) microg x g(-1), P < 0.05)]. But the expression of active t-PA was shown no significantly difference among the three groups. For MMP-2 and MMP-9 activity, they were significantly higher compared with the sham group in UUO group, but no significantly change after A&A treatment. The TIMP-1 activity was significantly increased in UUO group by 28% and 63% at day 7 and 10 respectively, significantly decreased in UAA group by 40% and 39% at the same time point. CONCLUSION: The anti-fibrosis effects of A&A might be associated with modulating the imbalance of PAs/PAIs system as well as MMPs/TIMPs system, thereby alleviate ECM accumulation and interstitial fibrosis.
目的：细胞外基质（ECM）合成与降解之间的失衡会导致ECM过度沉积，进而引发肾纤维化。由黄芪和当归两种中药组成的煎剂（A&A）已被证明可减轻慢性肾脏病动物模型中的ECM生成。本文研究了A&A对大鼠间质纤维化中ECM降解的影响。 方法：将雄性Wistar大鼠随机分为假手术组、单侧输尿管梗阻（UUO）组和UAA组（UUO加A&A给药）。通过灌胃给予A&A（14 g·kg⁻¹·d⁻¹）3、7和10天后，采用苏木精-伊红（HE）、过碘酸-雪夫（PAS）和天狼星红染色技术评估形态学变化。采用酶联免疫吸附测定（ELISA）法测定纤溶酶原激活物抑制剂-1（PAI-1）和组织型纤溶酶原激活物（t-PA）的表达、PAI-1和t-PA的活性。分别采用明胶酶谱法或反向明胶酶谱法评估基质金属蛋白酶（MMP-9、MMP-2）、基质金属蛋白酶组织抑制剂-1（TIMP-1）的活性。 结果：形态学分析显示，UUO组肾脏出现严重的间质单核细胞浸润、肾小管萎缩、肾纤维化和胶原表达，而A&A给药后这些情况有所减轻（P<0.05，UAA组与UUO组相比）。与假手术组相比，UUO组PAI-1的表达在第3、7和10天分别显著增加63%、91%和112%；而UAA组在第3、7和10天分别显著降低44%、43%和52%。活性PAI-1的表达在UUO组第3天显著增加[（30.5±23.8）ng·g⁻¹ 对 （0.0±0.0）ng·g⁻¹，P<0.05]、第7天[（36.5±11.2）ng·g⁻¹ 对 （0.0±0.0）ng·g⁻¹，P<
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