Shigatoxin 1 regulates vasoactive factor production by human glomerular epithelial cells

Postdiarrheal hemolytic uremic syndrome (D+HUS) is the leading cause of acute renal failure in children. Shigatoxin (Six) producing E. coli have been strongly implicated in the pathogenesis of D+HUS. Stx is thought to be responsible for many of the deleterious conditions associated with D+HUS, including reduced renal function and various nervous system disorders. The kidney appears to be a target organ for Stx. This observation has led to the finding of specific receptors for Stx in the glomerulus and tubules of the kidney. Histological examination of the kidneys of patients with HUS reveals glomerular thrombosis, cortical necrosis, accumulation of fibrin and endothelial cell swelling and detachment. However many HUS patients have reduced glomerular filtration rate and reduced renal function with none of these histological findings, suggesting the involvement of vasoactive factors in the pathogenesis of HUS. The glomerular epithelial cell (GEC) has emerged as a potential target of Stx in the kidney. Methods for culturing GEC were developed and the effects of Stx on these cells were studied. GEC were found to be very sensitive to Stx and to produce significant amounts of vasoactive eicosanoids in response to Stx. Because of the potentially deleterious effects of these eicosanoids, the cellular mechanisms by which they are produced were investigated. Phospholipase A2 (PLA2) and cyclooxygenase (COX) activities in GEC were measured and found to increase significantly in response to Stx.