CYTOTOXIC EFFECT OF SHIGA TOXIN-1 ON HUMAN PROXIMAL TUBULE CELLS

Background. Cytolytic Shiga toxins (Stx) are believed to be largely re sponsible for renal damage in post-diarrheal hemolytic-uremic syndrome (D+HUS). Despite the general belief that endothelial cells are the pr imary target of Stx, there is evidence that proximal tubules may be a site of toxin action. We hypothesized that cultured proximal tubular c ells are sensitive to the cytotoxic effects of Stx. Methods. Cultured human proximal tubular cells were exposed to Stx-1 in the presence and absence of a variety of inflammatory factors likely to be elevated in the kidney or serum of patients with D+HUS. Cell survival, protein sy nthesis, total cell levels and synthesis of Stx receptors (GB3), and S tx binding were measured. Results. Proximal tubules were extremely sen sitive to the cytotoxic effect of Stx-1 with an LD50 at least equal to , if not less than, that seen with Vero cells. Interleukin-1 (IL-1), l ipopolysaccharide (LPS), and butyrate (but not tumor necrosis factor o r interleukin-6) up-regulated proximal tubule sensitivity to Stx-1. IL -1 increased Stx-1 binding, but did not alter total cell levels or syn thesis of GB3, the glycosphingolipid receptor for Stx-1. In contrast, LPS and butyrate, despite increasing Stx-1 sensitivity, had no effect on Stx-1 binding. Conclusions. These studies indicate that proximal tu bules are exquisitely sensitive to Stx-1 cytotoxicity and that inflamm atory factors can increase toxin responsiveness through a variety of m echanisms. It is suggested that proximal tubules may be an important e arly target of Stx-1 action in D+HUS.