Effects of a glucosylceramide synthase inhibitor (C-9) on an experimental model of Hemolytic Uremic Syndrome in rats

SILBERSTEIN CLAUDIA; LUCERO MARÍA SOLEDAD; ZOTTA ELSA; REPETTO HORACIO A; IBARRA CRISTINA

Vancouver, Canadá

Congreso; Meeting of the Pediatric Academic Societies; 2010

Pediatric Academic Societies

BACKGROUND: Infections by Shiga toxin (Stx) producing E coli can induce watery and bloody diarrhea and hemolytic uremic syndrome (HUS). The pathogenesis of HUS is established by the lesion generated by the binding of Stx to its receptor globotriaosyl-ceramide (Gb3). We have recently observed that the C9 (Genzyme Co.), a specific inhibitor of glycosyl-ceramide synthase, decreases the expression of Gb3 and inhibits the cytotoxic effects of Stx type 2 (Stx2) in human kidney epithelial cells in culture (Silberstein et al., J Epithel Biol Pharmacol 1, 2008).OBJECTIVE: This study was designed to observe the in vivo effects of C9 in an experimental model of HUS in rats. Survival of the animals and histopathological changes in kidney, small bowel and colon were evaluated.DESIGN/METHODS: One group of male Sprague-Dawley rats (age: 4 weeks) were injected intraperitoneally with a filtered culture supernatant from recombinant E. coli expressing Stx2 (Stx2: 1ml/100g body weight, 1x104 CD50 in Vero cells; lipopolisacaride: 30ng/ml). A control group (Ctr) received the same filtrate which does not express the Stx2.A different group of rats were treated with C9 orally (10-15 mg/Kg/day) since 48 hours prior to the injections.RESULTS: All rats injected with Stx2 died between 48 and 72 hours after the injection. Treatment with C9 induced a survival of 50%. The other 50% died between 72 and 120 hours after the toxin injection. Rats given only C9 had a survival rate similar to Ctr. After 24 hours of the Stx2 injection the animals showed tubular and glomerular necrosis inthe kidney, edema and necrosis in the epithelium of the small bowel and a reduction of the globet cells in the colon. Treatment with C9 decreased the kidney lesions and suppressed completely the effects of the Stx2 in the intestine.CONCLUSIONS: The use of inhibitors of the synthesis of Gb3 could be a new therapeutic strategy to neutralize the deleterious effects of Stx and prevent the development of HUS.