ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Renal Pharmacology
This article is part of the Research TopicTubulopathies: Pathophysiological Insights and Advances in Therapeutic StrategiesView all 3 articles
Eliglustat prevents acute kidney injury caused by Shiga toxin 2 in rat lethal and sublethal models of Hemolytic Uremic Syndrome
Provisionally accepted
- Faculty of Medicine, University of Buenos Aires, Buenos Aires, Argentina
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Background: Shiga toxin-producing Escherichia coli is the main cause of post-diarrheal hemolytic uremic syndrome (HUS) which produces acute kidney injury mainly in children. Shiga toxin exerts its action by binding to the glycolipid globotriaosylceramide (Gb3) on the cell surface of target tissues. In humans, the kidneys are the organs most affected by Shiga toxin, where high Gb3 expression in glomerular endothelial and tubular epithelial cells leads to a combined glomerulopathy and tubulopathy that drive acute kidney injury. The aim of the present work was to evaluate the effectiveness of oral treatment with Eliglustat (EG), an inhibitor of glucosylceramide synthase, first step of glycosphingolipid biosynthesis, in preventing the effects of Shiga toxin 2 (Stx2) in lethal and sublethal models of HUS in rats. Methods: Male juvenile Sprague-Dawley rats (~100 g body weight (bw)) were intraperitoneally injected with lethal (5 ng/g bw) or sublethal (1 ng/g bw) doses of Stx2, or eluent. Some rats were orally treated with EG (15 or 25 mg/day) during 0-2 days prior until 2 or 3 days post-injection. Rat Survival, renal Gb3 expression, renal function, histopathological observations, as well as aquaporin 1 (AQP1) and neutrophil gelatinase-associated lipocalin (NGAL) tubular expression were evaluated. Results: Rats injected with Stx2 lethal dose showed significant kidney injury with extended tubular necrosis and some glomerular alterations, at 3 days post-injection. The Stx2 sublethal dose caused significantly lower renal injury extension than the lethal dose showing only tubular damage. The expression of AQP1 and NGAL corroborated the tubular alteration in Stx2-injected rats. The oral treatment with EG reduced Gb3 renal levels, and therefore, significantly prevented the renal injury caused by lethal and sublethal doses of Stx2 in rats. Moreover, the pre-treatment for two days with EG prevented the mortality in those rats injected with the Stx2 lethal dose. The EG treatment did not cause renal or systemic alterations. The effectiveness of EG treatment depended on the dose and the pretreatment time. Conclusions: The oral treatment with EG could be a therapeutic strategy to prevent the action of Stx2 and the development of acute kidney injury in diarrhea-associated HUS patients.
Keywords: Eliglustat, Globotriaosylceramide receptor, Glucosylceramide synthase inhibitor, Hemolytic uremic syndrome, renal tubular injury prevention, Shiga toxin type 2
Received: 30 Oct 2025; Accepted: 14 Jan 2026.
Copyright: © 2026 Sánchez, Fischer Sigel, Zotta and Silberstein. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Claudia Silberstein
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