Kagami S, Kuhara T, Okada K, Kuroda Y, Border W A, Noble N A
Department of Pediatrics, School of Medicine, University of Tokushima, Japan.
Kidney Int. 1997 Mar;51(3):664-71. doi: 10.1038/ki.1997.96.
Previous studies indicate that angiotensin II (Ang II) stimulates extracellular matrix synthesis through induction of transforming growth factor-beta (TGF-beta) expression. Here we investigate Ang II effects on the plasmin protease system. Plasmin both degrades extracellular matrix itself and activates metalloproteinases which then degrade collagens. Plasmin production is determined by the balance between plasminogen activators (PA) and their inhibitors (PAI-1,2). The data presented here indicate that Ang II treatment of mesangial cells in culture markedly increases PAI-1 gene transcription and PAI-1 mRNA levels but does not change the half life of PAI-1 mRNA. Increased PAI-1 protein was detected 24 hours after Ang II stimulation with a concomitant decrease of PA activity. To determine whether these effects were mediated by TGF-beta, cells were coincubated with Ang II and neutralizing antibody to TGF-beta. Induction of PAI-1 at four hours was not altered but the prolonged effect of Ang II on PAI-1 protein synthesis was markedly diminished. Thus, Ang II acts both through rapid, direct transcriptional up-regulation of the PAI-1 gene and through induction of TGF-beta, providing sustained changes in the PAI-1/PA system, which would favor extracellular matrix accumulation by inhibiting turnover. These data provide further evidence that Ang II can act as a potent fibrogenic molecule independent of its effects on blood pressure.
先前的研究表明，血管紧张素II（Ang II）通过诱导转化生长因子-β（TGF-β）表达来刺激细胞外基质合成。在此，我们研究Ang II对纤溶酶蛋白酶系统的影响。纤溶酶既能降解细胞外基质本身，又能激活金属蛋白酶，进而降解胶原蛋白。纤溶酶的产生取决于纤溶酶原激活剂（PA）与其抑制剂（PAI-1、2）之间的平衡。此处呈现的数据表明，在培养中用Ang II处理系膜细胞可显著增加PAI-1基因转录和PAI-1 mRNA水平，但不会改变PAI-1 mRNA的半衰期。在用Ang II刺激24小时后检测到PAI-1蛋白增加，同时PA活性降低。为了确定这些效应是否由TGF-β介导，将细胞与Ang II和抗TGF-β中和抗体共同孵育。4小时时PAI-1的诱导未改变，但Ang II对PAI-1蛋白合成的延长效应明显减弱。因此，Ang II既通过快速、直接上调PAI-1基因转录起作用，又通过诱导TGF-β起作用，从而使PAI-1/PA系统发生持续变化，这将通过抑制周转而有利于细胞外基质积累。这些数据进一步证明，Ang II可作为一种强效的致纤维化分子，与其对血压的影响无关。
