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 characterist ic of Shiga toxin-associated hemolytic uremic syndrome (HUS). An impai red renal fibrinolysis may be responsible for renal microvascular fibr in accumulation during the course of HUS disease. This study examined the effect of Shiga toxin, bacterial lipopolysaccharide (LPS, endotoxi n), and tumor necrosis factor (TNF) on the expression of fibrinolysis factors by human renal glomerular microvascular endothelial cells (HRM EC) in vitro. The results were compared to a previously better-charact erized endothelial cell type, human umbilical vein endothelial cells ( HUVEC). In HUVEC, the ratio of fibrinolysis antigens was antifibrinoly tic, consisting of 55-fold more plasminogen activator inhibitor type 1 (PAI-1) than tissue-type plasminogen activator (tPA). Treatment of HU VEC with LPS or TNF accentuated this ratio by decreasing tPA and incre asing PAI-1 expression. In contrast, HRMEC produced urokinase-type pla sminogen activator (uPA) in a 24-fold excess to PAI-1 and were thereby profibrinolytic with regard to fibrinolysis antigen expression. LPS a nd TNF further decreased PAI-1 antigen expression by HRMEC. These resu lts argue against a role for LPS or TNF in decreasing renal fibrinolys is 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 fibrinolys is 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 predisp ose renal microvasculature to thrombosis and may have implications for the development of HUS. (C) 1994 Academic Press, Inc.