组织型纤溶酶原激活剂在实验性肾小球肾炎中促进肾小球纤溶酶生成及基质降解。

t-PA promotes glomerular plasmin generation and matrix degradation in experimental glomerulonephritis.

作者信息

Haraguchi M, Border W A, Huang Y, Noble N A

机构信息

Fibrosis Research Laboratory, Division of Nephrology, University of Utah, Salt Lake City, Utah 84108, USA.

出版信息

Kidney Int. 2001 Jun;59(6):2146-55. doi: 10.1046/j.1523-1755.2001.00729.x.

DOI:10.1046/j.1523-1755.2001.00729.x

PMID:11380816

Abstract

BACKGROUND

In addition to its well-known role in degrading fibrin, recent evidence suggests that plasmin degrades matrix proteins and activates prometalloproteinases. Plasmin is generated from plasminogen by tissue plasminogen activator (t-PA). We hypothesized that t-PA treatment increases plasmin generation in nephritic glomeruli and degrades pathological matrix leading to a therapeutic reduction in matrix accumulation.

METHODS

Anti-Thy-1 nephritis was induced by injection of OX-7 antibody. Rats were given twice daily intravenous injections of saline (disease control group) or human recombinant t-PA (rt-PA; 1 mg/kg body weight) on days 3 through 5. Proteinuria, glomerular matrix protein staining, and glomerular mRNA levels for transforming growth factor-beta 1 (TGF-beta 1), fibronectin, and plasminogen activator inhibitor type 1 (PAI-1) were evaluated at day 6. Localization of rt-PA, plasmin generation by glomeruli in vitro, and glomerular production and content of active TGF-beta1 were also investigated.

RESULTS

Compared with disease control animals, proteinuria and staining score for periodic acid-Schiff (2.75 +/- 0.17 vs. 1.41 +/- 0.09), fibronectin-EDA+ (19 +/- 2 vs. 14 +/- 1), laminin (35 +/- 2 vs. 25 +/- 2), type I collagen (33 +/- 1 vs. 21 +/- 3), and type IV collagen (27 +/- 2 vs. 23 +/- 1) were significantly reduced in treated rats (P < 0.01). Glomerular TGF-beta 1, fibronectin, and PAI-1 mRNA levels were unchanged. rt-PA colocalized with fibrin along glomerular capillary walls and in the mesangium. Nephritic glomeruli in vitro had decreased plasmin activity, which was elevated by an in vivo presacrifice injection of rt-PA. Glomerular production and content of active TGF-beta 1 were unchanged by the rt-PA injection.

CONCLUSIONS

: These results show that injected rt-PA binds to fibrin in nephritic glomeruli, thus increasing plasmin generation and promoting pathological matrix degradation without activating latent TGF-beta. Agents that increase plasmin generation, such as t-PA, may have potential as antifibrotic therapies.

摘要

背景

除了其在降解纤维蛋白方面的知名作用外，最近的证据表明纤溶酶还能降解基质蛋白并激活前基质金属蛋白酶。纤溶酶由组织纤溶酶原激活物（t-PA）从纤溶酶原生成。我们推测t-PA治疗可增加肾炎性肾小球中的纤溶酶生成，并降解病理性基质，从而导致基质积聚的治疗性减少。

方法

通过注射OX-7抗体诱导抗Thy-1肾炎。在第3至5天，大鼠每天接受两次静脉注射生理盐水（疾病对照组）或人重组t-PA（rt-PA；1mg/kg体重）。在第6天评估蛋白尿、肾小球基质蛋白染色以及转化生长因子-β1（TGF-β1）、纤连蛋白和纤溶酶原激活物抑制剂1型（PAI-1）的肾小球mRNA水平。还研究了rt-PA的定位、体外肾小球的纤溶酶生成以及活性TGF-β1的肾小球产生和含量。

结果

与疾病对照动物相比，治疗组大鼠的蛋白尿和高碘酸-希夫染色评分（2.75±0.17对1.41±0.09）、纤连蛋白-EDA+（19±2对14±1）、层粘连蛋白（35±2对25±2）、I型胶原（33±1对21±3）和IV型胶原（27±2对23±1）显著降低（P<0.01）。肾小球TGF-β1、纤连蛋白和PAI-1 mRNA水平未改变。rt-PA与纤维蛋白在肾小球毛细血管壁和系膜中共定位。体外肾炎性肾小球的纤溶酶活性降低，而体内注射rt-PA进行预处死可提高该活性。rt-PA注射后，活性TGF-β-1的肾小球产生和含量未改变。