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      Apoptosis of Renal Tubular Cells in Shiga-Toxin-Mediated Hemolytic Uremic Syndrome

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          Abstract

          In order to clarify the mechanism of unusual renal tubular dysfunction seen in a child with Shiga toxin (Stx)-mediated hemolytic uremic syndrome (HUS), we studied the renal biopsy specimens for Stx binding and apoptosis of renal tubular cells. A 7-year-old boy with Stx-2-mediated HUS demonstrated extensive renal tubular damage characterized by nonoliguric acute renal failure, increased urinary tubular enzymes and defective urine-concentrating capacity. His renal biopsy specimens were analyzed for Stx binding and apoptotic cell death. Seven kidney tissue specimens obtained from patients without HUS served as controls. Detection of Stx binding to renal sections and apoptotic cells were performed using mouse monoclonal anti-Stx 2 antibody and the TUNEL method, respectively. Positive staining was observed predominantly in renal tubular cells, while the 7 kidney tissue specimens from control patients did not show positive staining. To the best of our knowledge, this is the first case to show Stx binding and apoptotic cell death in renal tubules on biopsy specimens obtained from a child with Stx-mediated HUS. In conclusion, this case suggests that vascular endothelial cells are not the sole nor the consistent target for Stx-mediated cell injury and that significant renal tubular damage other than glomerular damage might occur in some children with Stx-mediated HUS.

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          Most cited references 2

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          Cytotoxic effect of Shiga toxin-1 on human proximal tubule cells.

          Cytolytic Shiga toxins (Stx) are believed to be largely responsible for renal damage in post-diarrheal hemolytic-uremic syndrome (D + HUS). Despite the general belief that endothelial cells are the primary target of Stx, there is evidence that proximal tubules may be a site of toxin action. We hypothesized that cultured proximal tubular cells are sensitive to the cytotoxic effects of Stx. Cultured human proximal tubular cells were exposed to Stx-1 in the presence and absence of a variety of inflammatory factors likely to be elevated in the kidney or serum of patients with D + HUS. Cell survival, protein synthesis, total cell levels and synthesis of Stx receptors (GB3), and Stx binding were measured. Proximal tubules were extremely sensitive to the cytotoxic effect of Stx-1 with an LD50 at least equal to, if not less than, that seen with Vero cells. Interleukin-1 (IL-1), lipopolysaccharide (LPS), and butyrate (but not tumor necrosis factor or interleukin-6) up-regulated proximal tubule sensitivity to Stx-1. IL-1 increased Stx-1 binding, but did not alter total cell levels or synthesis of GB3, the glycosphingolipid receptor for Stx-1. In contrast, LPS and butyrate, despite increasing Stx-1 sensitivity, had no effect on Stx-1 binding. These studies indicate that proximal tubules are exquisitely sensitive to Stx-1 cytotoxicity and that inflammatory factors can increase toxin responsiveness through a variety of mechanisms. It is suggested that proximal tubules may be an important early target of Stx-1 action in D + HUS.
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            Verotoxins induce apoptosis in human renal tubular epithelium derived cells.

            Apoptosis mediated by verotoxins (VTs) has been identified in a renal carcinoma cell line, ACHN cells, which are an in vitro model of renal tubular epithelial cells. ACHN cells express the renal tubular marker CD24 as well as globotriaosyl ceramide/CD77, the receptor for VTs. VT binding to the ACHN cell surface was confirmed by positive staining with antibodies to the VTs. Treatment of ACHN cells with VTs induced prompt growth inhibition and cell death, and fragmentation of the genomic DNA in cells, typical of apoptosis, was observed. The expression of apoptotic antigen 7A6 detected by APO2.7 antibody in ACHN cells further supports the occurrence of apoptosis as a result of VT treatment. Cycloheximide enhanced VT-mediated apoptosis of ACHN cells, suggesting a strong correlation between the inhibition of protein synthesis and VT-mediated apoptosis. Moreover, tumor necrosis factor-alpha had a synergistic effect on VT-mediated apoptosis in ACHN cells. Considering the above evidence together with the clinical evidence showing the presence of apoptosis in the renal epithelium of a HUS patient, our results suggest a VT-induced apoptotic mechanism in normal renal tubular epithelium that may contribute to the pathogenesis of hemolytic uremic syndrome.
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              Author and article information

              Journal
              NEF
              Nephron
              10.1159/issn.1660-8151
              Nephron
              S. Karger AG
              1660-8151
              2235-3186
              2001
              2001
              16 February 2001
              : 87
              : 2
              : 182-185
              Affiliations
              aDepartment of Pediatrics, Juntendo University School of Medicine, Departments of bPathology and cInfectious Disease Research, National Children’s Hospital Research Center, Tokyo, Japan
              Article
              45909 Nephron 2001;87:182–185
              10.1159/000045909
              11244315
              © 2001 S. Karger AG, Basel

              Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

              Page count
              Figures: 1, References: 15, Pages: 4
              Product
              Self URI (application/pdf): https://www.karger.com/Article/Pdf/45909
              Categories
              Short Communication

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