Moll S, Menoud P A, Fulpius T, Pastore Y, Takahashi S, Fossati L, Vassalli J D, Sappino A P, Schifferli J A, Izui S
Department of Pathology, University of Geneva Medical School, Switzerland.
Kidney Int. 1995 Nov;48(5):1459-68. doi: 10.1038/ki.1995.435.
Three major components of the plasminogen activators (PA)/plasmin system are synthesized physiologically in glomeruli, and can be involved in glomerular proteolysis and extracellular matrix metabolism: tissue-type PA (tPA), urokinase (uPA) and PA inhibitor type 1 (PAI-1). To explore the possible role of a dysregulation of the plasmin protease system in the development and progression of lupus-like glomerulonephritis, we studied the expression of the renal plasmin protease components during the course of the disease, either acute, induced by IgG3 monoclonal cryoglobulins, or chronic, occurring spontaneously in three different lupus-prone mice: (NZBxNZW)F1, BXSB and MRL-lpr/lpr. RNase protection assays and in situ hybridizations revealed a marked glomerular induction of PAI-1 mRNA abundance without any significant changes in renal tPA and uPA mRNA levels in the two different types of lupus-like glomerulonephritis. The overexpression of PAI-1 mRNA occurred in parallel with a significant decrease in glomerular tPA-catalyzed enzymatic activity as determined by zymographic analysis. In addition, a concomitant increase in glomerular expression of transforming growth factor beta 1 (TGF-beta 1) mRNA was observed. The demonstration of a close correlation between the PAI-1 and TGF-beta 1 mRNA levels and the severity of lupus-like glomerular lesions suggests that a pertubation of the glomerular PA/PAI balance, resulting from a marked TGF-beta 1-mediated induction of PAI-1 gene expression, plays an important role in the progression of lupus-like glomerular lesions, leading to glomerulosclerosis.
纤溶酶原激活剂（PA）/纤溶酶系统的三个主要成分在肾小球中生理性合成，并可参与肾小球蛋白水解和细胞外基质代谢：组织型PA（tPA）、尿激酶（uPA）和1型PA抑制剂（PAI-1）。为了探究纤溶蛋白酶系统失调在狼疮样肾小球肾炎发生和发展中的可能作用，我们研究了在该疾病过程中肾纤溶蛋白酶成分的表达，该疾病要么是由IgG3单克隆冷球蛋白诱导的急性疾病，要么是在三种不同的狼疮易感小鼠：（NZBxNZW）F1、BXSB和MRL-lpr/lpr中自发发生的慢性疾病。核糖核酸酶保护分析和原位杂交显示，在两种不同类型的狼疮样肾小球肾炎中，PAI-1 mRNA丰度在肾小球中有显著诱导，而肾tPA和uPA mRNA水平没有任何显著变化。PAI-1 mRNA的过表达与通过酶谱分析测定的肾小球tPA催化酶活性的显著降低同时发生。此外，还观察到转化生长因子β1（TGF-β1）mRNA在肾小球中的表达同时增加。PAI-1和TGF-β1 mRNA水平与狼疮样肾小球病变严重程度之间密切相关性的证明表明，由显著的TGF-β1介导的PAI-1基因表达诱导导致的肾小球PA/PAI平衡紊乱在狼疮样肾小球病变的进展中起重要作用，导致肾小球硬化。
