Louise C B, Obrig T G
Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, New York 14642.
Microvasc Res. 1994 May;47(3):377-87. doi: 10.1006/mvre.1994.1030.
Renal glomerular microvascular endothelial cell damage is characteristic of Shiga toxin-associated hemolytic uremic syndrome (HUS). An impaired renal fibrinolysis may be responsible for renal microvascular fibrin accumulation during the course of HUS disease. This study examined the effect of Shiga toxin, bacterial lipopolysaccharide (LPS, endotoxin), and tumor necrosis factor (TNF) on the expression of fibrinolysis factors by human renal glomerular microvascular endothelial cells (HRMEC) in vitro. The results were compared to a previously better-characterized endothelial cell type, human umbilical vein endothelial cells (HUVEC). In HUVEC, the ratio of fibrinolysis antigens was antifibrinolytic, consisting of 55-fold more plasminogen activator inhibitor type 1 (PAI-1) than tissue-type plasminogen activator (tPA). Treatment of HUVEC with LPS or TNF accentuated this ratio by decreasing tPA and increasing PAI-1 expression. In contrast, HRMEC produced urokinase-type plasminogen activator (uPA) in a 24-fold excess to PAI-1 and were thereby profibrinolytic with regard to fibrinolysis antigen expression. LPS and TNF further decreased PAI-1 antigen expression by HRMEC. These results argue against a role for LPS or TNF in decreasing renal fibrinolysis at the level of fibrinolysis factor expression by renal endothelial cells. Nevertheless, HUVEC and HRMEC were responsive to the same LPS analogs in the same order of potency. Shiga toxin decreased fibrinolysis factor expression to a greater extent in HRMEC than in HUVEC. Since HRMEC fibrinolysis antigen expression was profibrinolytic, the Shiga toxin-mediated decrease in renal endothelial uPA synthesis may predispose renal microvasculature to thrombosis and may have implications for the development of HUS.
肾肾小球微血管内皮细胞损伤是志贺毒素相关溶血尿毒综合征（HUS）的特征。肾纤维蛋白溶解功能受损可能是HUS病程中肾微血管纤维蛋白积聚的原因。本研究在体外检测了志贺毒素、细菌脂多糖（LPS，内毒素）和肿瘤坏死因子（TNF）对人肾肾小球微血管内皮细胞（HRMEC）纤维蛋白溶解因子表达的影响。将结果与之前特征更明确的内皮细胞类型人脐静脉内皮细胞（HUVEC）进行比较。在HUVEC中，纤维蛋白溶解抗原的比例是抗纤维蛋白溶解的，纤溶酶原激活物抑制剂1型（PAI-1）比组织型纤溶酶原激活物（tPA）多55倍。用LPS或TNF处理HUVEC会通过降低tPA和增加PAI-1表达来加剧这一比例。相比之下，HRMEC产生的尿激酶型纤溶酶原激活物（uPA）比PAI-1多24倍，因此就纤维蛋白溶解抗原表达而言具有促纤维蛋白溶解作用。LPS和TNF进一步降低了HRMEC的PAI-1抗原表达。这些结果表明，LPS或TNF在肾内皮细胞纤维蛋白溶解因子表达水平上降低肾纤维蛋白溶解方面不起作用。然而，HUVEC和HRMEC对相同的LPS类似物以相同的效力顺序产生反应。志贺毒素在HRMEC中比在HUVEC中更能降低纤维蛋白溶解因子的表达。由于HRMEC纤维蛋白溶解抗原表达具有促纤维蛋白溶解作用，志贺毒素介导的肾内皮细胞uPA合成减少可能使肾微血管易形成血栓，并可能对HUS的发展产生影响。
