Multifunctionality of PAI-1 in fibrogenesis:: Evidence from obstructive nephropathy in PAI-1-overexpressing mice
Multifunctionality of PAI-1 in fibrogenesis:: Evidence from obstructive nephropathy in PAI-1-overexpressing mice
复制标题
DOI：
10.1111/j.1523-1755.2005.00327.x
复制
发表时间：
2005-06-01
影响因子：
19.6
通讯作者：
Eddy, AA
中科院分区：
文献类型：
--
作者：
Matsuo, S;López-Guisa, JM;Eddy, AA
背景纤溶酶原激活物抑制剂-1（派-1）在慢性肾脏疾病的发病机制中有牵连，这是基于其上调表达以及实验模型中派-1抑制或耗竭的有益作用。派-1是一种多功能蛋白，其促纤维化作用的机制尚未完全阐明。本研究旨在通过比较C57 BL 6背景下PAI-1过表达小鼠（派-1 tg）和野生型小鼠单侧输尿管梗阻模型（UUO）（第3、7和14天）来研究派-1依赖性纤维化途径。UUO后，派-1 tg小鼠（N = 6至8/组）的总肾脏派-1 mRNA和/或蛋白水平显著更高，纤维化严重程度显著更差（第3、7和14天），均以天狼星红阳性间质面积（例如，10 +/- 3.2%对比4.5 +/- 1.0%）（第14天）和总肾胶原蛋白（例如，11.1+/- 1.7 vs. 6.2 +/- 1.3 μ g/mg）（第14天）。到第14天，派-1 tg小鼠中两种正常肾小管蛋白E-钙粘蛋白和Ksp-钙粘蛋白的表达显著降低（分别为3.2 +/- 0.5% vs. 11.7 +/- 5.9%和2.6 +/- 1.6 vs. 6.2 +/-0.8%），这意味着更广泛的肾小管损伤。派-1 tg小鼠中至少有四种纤维化途径差异表达。首先，间质巨噬细胞募集更强烈（P < 0.05第3和14天）。第二，间质肌成纤维细胞密度更大（P < 0.05第3和7天），尽管数量相似的小管间质细胞增殖。第三，转化生长因子-β 1（TGF-β 1）和I型胶原mRNA显著升高。最后，尽管mRNA水平相似，但尿激酶活性显著降低（P < 0.05，第7天和第14天）。基因芯片研究表明，该促纤维化基因的缺失对慢性肾损伤的肾细胞反应具有深远的影响。这些数据提供了进一步的证据，派-1通过两种主要的重叠机制直接参与间质纤维化和肾小管损伤：对间质细胞募集的早期效应和与尿激酶活性降低相关的晚期效应。
Background. Plasminogen activator inhibitor-1 (PAI-1) has been implicated in the pathogenesis of chronic kidney disease based on its up-regulated expression and on the beneficial effects of PAI-1 inhibition or depletion in experimental models. PAI-1 is a multifunctional protein and the mechanisms that account for its profibrotic effects have not been fully elucidated.Methods. The present study was designed to investigate PAI-1-dependent fibrogenic pathways by comparing the unilateral ureteral obstruction model (UUO) (days 3, 7, and 14) in PAI-I-overexpressing mice (PAI-1 tg) to wild-type mice, both on a C57BL6 background.Results. Following UUO, total kidney PAI-1 mRNA and/or protein levels were significantly higher in the PAI-1 tg mice (N = 6 to 8/group) and fibrosis severity was significantly worse (days 3, 7, and 14), measured both as Sirius red-positive interstitial area (e.g., 10 +/- 3.2% vs. 4.5 +/- 1.0%) (day 14) and total kidney collagen (e.g., 11.1 +/- 1.7 vs. 6.2 +/- 1.3 mu g/mg) (day 14). By day 14, the expression of two normal tubular proteins, E-cadherin and Ksp-cadherin, were significantly lower in the PAI-1 tg mice (3.2 +/- 0.5% vs. 11.7 +/- 5.9% and 2.6 +/- 1.6) vs. 6.2 +/- 0.8%, respectively), implying more extensive tubular damage. At least four fibrogenic pathways were differentially expressed in the PAI-1 tg mice. First, interstitial macrophage recruitment was more intense (P < 0.05 days 3 and 14). Second, interstitial myofibroblast density was greater (P < 0.05 days 3 and 7) despite similar numbers of proliferating tubulointerstitial cells. Third, transforming growth factor-beta 1 (TGF-beta 1) and collagen I mRNA were significantly higher. Finally, urokinase activity was significantly lower (P < 0.05 days 7 and 14) despite similar mRNA levels. Gene microarray studies documented that that the deletion of this single profibrotic gene had far-reaching consequences on renal cellular responses to chronic injury.Conclusion. These data provide further evidence that PAI-1 is directly involved in interstitial fibrosis and tubular damage via two primary overlapping mechanisms: early effects on interstitial cell recruitment and late effects associated with decreased urokinase activity.