The hemolytic uremic syndrome is an important cause of acute renal failure and is often associated with prior infection with enterotoxigenic strains of Escherichia coli. Significant pathologic changes in the glomerulus include endothelial cell swelling, detachment, and intravascular coagulation. We investigated the potential pathogenetic mechanisms of this disease by exposing cultured rat glomerular endothelial cells to shiga-like toxin 1 (SLT-1). Glomerular endothelial cell viability and protein synthesis were not affected by 10–9 M SLT-1. Synthesis and release of thromboxane (Tx) A2, measured as the stable metabolite TxB2, and of 12-(S)-HETE were each increased 1.6 ± 0.1 fold (p < 0.05). No change was observed in the production of PGE2 or 6-keto-PGF1α, the active metabolite of PGI2. SLT-1 (10–9 M) significantly increased cell retraction and the formation of gaps in the glomerular endothelial cell monolayer for up to 6 h following exposure. A similar effect was seen with 0.1 μM 12-(S)-HETE. SLT-1 and 0.01 μM 12-(S)-HETE also significantly decreased adhesion of glomerular endothelial cells to fibronectin (75 ± 4 and 65 ± 2% of control, respectively; p < 0.001) and laminin (81 ± 5 and 67 ± 4% of control, respectively; p < 0.01). These results support a role for SLT-1 in the production of the pathologic changes seen in the hemolytic uremic syndrome through stimulation of production of procoagulant, vasoconstrictor arachidonic acid metabolites with potential to produce endothelial injury and through alterations in glomerular endothelial cell adhesion to components of the glomerular basement membrane.

Keywords:
Glomerular endothelial cell, Hemolytic uremic syndrome, Shiga-like toxin, Verotoxin
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1998
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