Background: Although Shiga toxin (Stx) mediates classical hemolytic uremic syndrome (HUS), it is not fully understood why only some subjects exposed to Stx-expressing Escherichia coli develop HUS. We have previously shown in a baboon model of Stx-mediated HUS that coadministration of lipopolysaccharide (LPS) results in an augmented host response to otherwise subtoxic Stx1 doses. We used this model to test the hypothesis that LPS upregulates renal Stx receptor (Gb3) expression. Methods: Juvenile baboons were treated with either Stx1 (100 ng/kg), LPS (1 mg/kg as two divided doses 24 h apart), or a sham injection of saline, and sacrificed and immediately autopsied at 72 h. Renal cortical tissue Gb3 content was quantitated by lipid extraction and thin-layer chromatography, and Stx1 and Gb3/CD77 immunostaining was assessed by quantitative immunofluorescent microscopy. Results: Compared to saline-in jected controls, LPS administration resulted in a 2.2-fold increase in renal cortical Gb3 by chromatography (p < 0.01), a 2.5-fold increase in Stx1 staining (p = 0.003) and a 1.7-fold increase in CD77 immunostaining (p = 0.004). Stx treatment did not significantly alter either Stx or CD77 immunostaining. Conclusion: These observations suggest that LPS primes the host for Stx-mediated renal injury by upregulating renal Gb3 expression.

1.
Siegler RL: The hemolytic uremic syndrome. Pediatr Clin North Am 1995;42:1505&ndash;1529.
2.
Tesh VL, Burris JA, Owens JW, Gordon VM, Wadolkowski EA, O&rsquo;Brien AD, Samuel JE: Comparison of the relative toxicities of Shiga-like toxins type I and type II for mice. Infect Immun 1993;61:3392&ndash;3402.
3.
Pai CH, Kelly JK, Meyers GL: Experimental infection of infant rabbits with verotoxin-producing Escherichia coli. Infect Immun 1986;51:16&ndash;23.
4.
Taylor FB Jr, Tesh VL, DeBault L, Li A, Chang AC, Kosanke SD, Pysher TJ, Siegler RL: Characterization of the baboon responses to Shiga-like toxin: descriptive study of a new primate model of toxic responses to Stx-1. Am J Pathol 1999;154:1285&ndash;1299.
5.
Siegler RL, Pysher TJ, Tesh VL, Taylor FB Jr: Response to single and divided doses of Shiga toxin-1 in a primate model of hemolytic uremic syndrome. J Am Soc Nephrol 2001;12:1458&ndash;1467.
6.
Siegler RL, Pysher TJ, Lou R, Tesh VL, Taylor FB Jr: Response to Shiga toxin-1, with and without lipopolysaccharide, in a primate model of hemolytic uremic syndrome. Am J Nephrol 2001;21:420&ndash;425.
7.
Koster F, Levin J, Walker L, Tung KS, Gilman RH, Rahaman MM, Majid MA, Islam S, Williams RC Jr: Hemolytic-uremic syndrome after shigellosis. Relation to endotoxemia and circulating immune complexes. N Engl J Med 1978;298:927&ndash;933.
8.
Coratelli P, Buongiorno E, Passavanti G: Endotoxemia in hemolytic uremic syndrome. Nephron 1988;50:365&ndash;367.
9.
Bitzan M, Moebius E, Ludwig K, Muller-Wiefel DE, Heesemann J, Karch H: High incidence of serum antibodies to Escherichia coli O157 lipopolysaccharide in children with hemolytic-uremic syndrome. J Pediatr 1991;119:380&ndash;385.
10.
Heyderman RS, Fitzpatrick MM, Barclay GR: Haemolytic-uraemic syndrome. Lancet 1994;343:1042.
11.
Kita E, Yunou Y, Kurioka T, Harada H, Yoshikawa S, Mikasa K, Higashi N: Pathogenic mechanism of mouse brain damage caused by oral infection with Shiga toxin-producing Escherichia coli O157:H7. Infect Immun 2000;68:1207&ndash;1214.
12.
Obrig TG, Louise CB, Lingwood CA, Boyd B, Barley-Maloney L, Daniel TO: Endothelial heterogeneity in Shiga toxin receptors and responses. J Biol Chem 1993;268:15484&ndash;15488.
13.
van Setten PA, van Hinsbergh VW, van der Velden TJ, van de Kar NC, Vermeer M, Mahan JD, Assmann KJ, van den Heuvel LP, Monnens LA: Effects of TNF alpha on verotoxin cytotoxicity in purified human glomerular microvascular endothelial cells. Kidney Int 1996;51:1245&ndash;1256.
14.
Stricklett PK, Hughes AK, Ergonul Z, Kohan DE: Molecular basis for up-regulation by inflammatory cytokines of Shiga toxin 1 cytotoxicity and globotriaosylceramide expression. J Infect Dis 2002;186:976&ndash;982.
15.
Tesh VL, Ramegowda B, Samuel JE: Purified Shiga-like toxins induce expression of proinflammatory cytokines from murine peritoneal macrophages. Infect Immun 1994;62:5085&ndash;5094.
16.
Ergonal Z, Clayton F, Fogo AB, Kohan DE: Shigatoxin-1 binding and receptor expression in human kidneys do not change with age. Pediatr Nephrol 2003;18:246&ndash;253.
17.
Hughes AK, Stricklett PK, Kohan DE: Cytotoxic effect of Shiga toxin-1 on human proximal tubule cells. Kidney Int 1998;54:426&ndash;437.
18.
Inward CD, Howie AJ, Fitzpatrick MM, Rafaat F, Milford DV, Taylor CM: Renal histopathology in fatal cases of diarrhoea-associated haemolytic uraemic syndrome. British Association for Paediatric Nephrology. Pediatr Nephrol 1997;11:556&ndash;559.
19.
Uchida H, Kiyokawa N, Horie H, Fujimoto J, Takeda T: The detection of Shiga toxins in the kidney of a patient with hemolytic uremic syndrome. Pediatr Res 1999;45:133&ndash;137.
20.
Siegler RL, Edwin SS, Christofferson RD, Mitchell MD: Plasma and urinary cytokines in the childhood hemolytic uremic syndrome (HUS) (abstract). J Am Soc Nephrol 1991;2:274.
21.
Karpman D, Andreasson A, Thysell H, Kaplan BS, Svanborg C: Cytokines in childhood hemolytic uremic syndrome and thrombotic thrombocytopenic purpura. Pediatr Nephrol 1995;9:694&ndash;699.
22.
Walker R, Fletcher J: Evidence that Injury to Platelets Can Contribute to the Diversity of Host Responses to Endotoxin. Amsterdam, Elsevier, Biomedical Press, 1980.
23.
Roth RI: Hemoglobin enhances the production of tissue factor by endothelial cells in response to bacterial endotoxin. Blood 1994;83:2860&ndash;2865.
24.
Palermo M, Alves-Rosa F, Rubel C, Fernandez GC, Fernandez-Alonso G, Alberto F, Rivas M, Isturiz M: Pretreatment of mice with lipopolysaccharide (LPS) or IL-1&beta; exerts dose-dependent opposite effects on Shiga toxin-2 lethality. Clin Exp Immunol 2000;119:77&ndash;83.
25.
Barrett TJ, Potter ME, Wachsmuth IK: Bacterial endotoxin both enhances and inhibits the toxicity of Shiga-like toxin II in rabbits and mice. Infect Immun 1989;57:3434&ndash;3437.
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