A Glucosylceramide Synthase Inhibitor Prevents the Cytotoxic Effects of Shiga Toxin-2 on Human Renal Tubular Epithelial Cells

Shiga toxin-2 binds to the globotriaosyl-ceramide receptor on the plasma membrane of target cells. The high level expression of this receptor in renal epithelial cells may account, at least in part, for acute renal failure observed in children with hemolytic uremic syndrome. The cytotoxic effect of Shiga toxin-2 was assayed on primary cultures of human renal tubular epithelial cells treated with a new specific inhibitor of glucosylceramide synthase (C-9), the ratelimiting first step in the glycosphingolipid biosynthetic pathway. The treatment of the cells with 1-5 [mu]M C-9 for at least 24 h significantly neutralized the action of 1 ng/ml Shiga toxin-2 on cell viability. The expression levels of globotriaosylceramide significantly decreased when cells were incubated with 1 [mu]M C-9 for 48 h. We propose here that prevention of globotriaosyl-ceramide synthesis by the C-9 could be a novel substrate inhibition therapy to neutralize Shiga toxin-2 action in renal epithelial cells.