title: A glucosylceramide synthase inhibitor protects rats against the cytotoxic effects of shiga toxin 2.
abstract: Postdiarrhea hemolytic uremic syndrome is the most common cause of acute renal failure in children in Argentina. Renal damage has been strongly associated with Shiga toxin (Stx), which binds to the globotriaosylceramide (Gb3) receptor on the plasma membrane of target cells. The purpose of the study was to evaluate the in vivo effects of C-9, a potent inhibitor of glucosylceramide synthase and Gb3 synthesis, on kidney and colon in an experimental model of hemolytic uremic syndrome in rats. Rats were i.p. injected with supernatant from recombinant Escherichia coli expressing Stx2 (sStx2). A group of these rats were orally treated with C-9 during 6 d, from 2 d prior until 4 d after sStx2 injection. The injection of sStx2 caused renal damage as well as a loss of goblet cells in colonic mucosa. Oral treatment with C-9 significantly decreased rat mortality to 50% and reduced the extension of renal and intestinal injuries in the surviving rats. The C-9 also decreased Gb3 and glucosylceramide expression levels in rat kidneys. It is particularly interesting that an improvement was seen when C-9 was administered 2 d before challenge, which makes it potentially useful for prophylaxis.
authors.affiliation: Laboratorio de Fisiopatogenia, Departamento de Fisiología, Facultad de Medicina, Universidad de Buenos Aires, 1121 Buenos Aires, Argentina. csilber@fmed.uba.ar
authors.forename: Claudia
authors.initials: C
authors.lastname: Silberstein
authors.forename: María S
authors.initials: MS
authors.lastname: Lucero
authors.forename: Elsa
authors.initials: E
authors.lastname: Zotta
authors.forename: Diane P
authors.initials: DP
authors.lastname: Copeland
authors.forename: Li
authors.initials: L
authors.lastname: Lingyun
authors.forename: Horacio A
authors.initials: HA
authors.lastname: Repetto
authors.forename: Cristina
authors.initials: C
authors.lastname: Ibarra
mesh_terms: D000284:Administration, Oral; D000818:Animals; D015415:Biomarkers / Q000097:blood; D003106:Colon / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D003404:Creatinine / Q000097:blood; D004146:Dioxanes / Q000494:pharmacology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006463:Hemolytic-Uremic Syndrome / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D022641:Shiga Toxin 2; D013997:Time Factors; D014281:Trihexosylceramides / Q000378:metabolism*; D014508:Urea / Q000097:blood
chemical_list: C520404:(2-(2',3'-dihydrobenzo(1,4)dioxin-6'-yl)-2-hydroxy-1-pyrrolidin-1-ylmethylethyl)nonanoic acid amide; D015415:Biomarkers; D004146:Dioxanes; D004791:Enzyme Inhibitors; D011759:Pyrrolidines; D022641:Shiga Toxin 2; D014281:Trihexosylceramides; C018549:globotriaosylceramide; D014508:Urea; D003404:Creatinine; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase