Human renal microvascular endothelial cells as a potential target in the development of the hemolytic uremic syndrome as related to fibrinolysis factor expression, in vitro.
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.
Louise
C B
CB
Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, New York 14642.
Obrig
T G
TG
D001427:Bacterial Toxins / Q000494:pharmacology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005342:Fibrinolysis / Q000187:drug effects / Q000502:physiology*; D006463:Hemolytic-Uremic Syndrome / Q000209:etiology*; D006801:Humans; D066298:In Vitro Techniques; D007678:Kidney Glomerulus / Q000098:blood supply*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008833:Microcirculation / Q000166:cytology / Q000378:metabolism; D009928:Organ Specificity; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis; D022603:Shiga Toxins; D010959:Tissue Plasminogen Activator / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis
D001427:Bacterial Toxins; D008070:Lipopolysaccharides; D017395:Plasminogen Activator Inhibitor 1; D022603:Shiga Toxins; D014409:Tumor Necrosis Factor-alpha; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator