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      Prenatal Exposure to High Level of Glucocorticoids Increases the Susceptibility of Renal Proximal Tubular Cells to Apoptosis Induced by Uropathogenic Escherichia coli Toxins

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          Prenatal exposure to excessive glucocorticoids may alter the developing fetus inducing metabolic and endocrine imbalance in various organs, including the kidney. This study aimed at evaluating whether prenatal exposure to high levels of glucocorticoids adversely affects renal cell survival and predisposes to renal cell death. Pregnant rats were injected with 0.1 mg/kg dexamethasone (DEX) i.p. from day 1 of gestation. Renal proximal tubular cells (PTCs) were prepared from 20-day-old offspring in the DEX (DEX cells) and control groups (CON cells). After 4 days’ culture, cells were exposed to uropathogenic Escherichia coli ARD6 toxins at concentrations known to induce apoptotic cell death. We found that cell death rate was significantly higher in DEX than in CON cells. Cells exhibited morphological and biochemical features of apoptosis. Conversely, the activity of the antioxidant enzyme catalase was significantly increased in renal cortex homogenate from 20-day-old DEX rats. The antioxidant vitamin E did not prevent apoptosis. These results indicate that prenatal exposure to high levels of glucocorticoids induces alterations in renal PTCs rendering them more sensitive to E. coli toxins via nonoxidative stress. With the increasing use of multiple doses of glucocorticoids in preterm infants, the possibility that antenatal glucocorticoids may lead to renal adverse consequences is of clinical relevance.

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          Most cited references 20

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          In utero programming of chronic disease.

          1. Many human fetuses have to adapt to a limited supply of nutrients. In doing so they permanently change their structure and metabolism. 2. These 'programmed' changes may be the origins of a number of diseases in later life, including coronary heart disease and the related disorders stroke, diabetes and hypertension. 3. This review examines the evidence linking these diseases to fetal undernutrition and provides an overview of previous studies in this area.
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            Identification of a novel hypoxia-inducible factor 1-responsive gene, RTP801, involved in apoptosis.

            Hypoxia is an important factor that elicits numerous physiological and pathological responses. One of the major gene expression programs triggered by hypoxia is mediated through hypoxia-responsive transcription factor hypoxia-inducible factor 1 (HIF-1). Here, we report the identification and cloning of a novel HIF-1-responsive gene, designated RTP801. Its strong up-regulation by hypoxia was detected both in vitro and in vivo in an animal model of ischemic stroke. When induced from a tetracycline-repressible promoter, RTP801 protected MCF7 and PC12 cells from hypoxia in glucose-free medium and from H(2)O(2)-triggered apoptosis via a dramatic reduction in the generation of reactive oxygen species. However, expression of RTP801 appeared toxic for nondividing neuron-like PC12 cells and increased their sensitivity to ischemic injury and oxidative stress. Liposomal delivery of RTP801 cDNA to mouse lungs also resulted in massive cell death. Thus, the biological effect of RTP801 overexpression depends on the cell context and may be either protecting or detrimental for cells under conditions of oxidative or ischemic stresses. Altogether, the data suggest a complex type of involvement of RTP801 in the pathogenesis of ischemic diseases.
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              Prevention of hypoxia-induced cell death by Bcl-2 and Bcl-xL.

              The proto-oncogene bcl-2, isolated from the t(14;18) chromosomal breakpoint in follicular B-lymphoma, and a bcl-2-related gene bcl-x (ref. 4) prevent apoptotic cell death induced by various treatments. Although a mechanism has been proposed that involves Bcl-2 activity on reactive oxygen species (ROS), expression of Bcl-2 or Bcl-xL prevents cell death induced by withdrawal of oxygen (hypoxia), which drastically decreases the net formation of oxygen free radicals and does not increase oxidized lipid, protein or DNA. Furthermore, neither ROS scavenger nor inhibitor of ROS scavenger affects cell death, regardless of the expression of Bcl-2 or Bcl-xL. Thus our data suggest that Bcl-2 and Bcl-xL exert an anti-cell death function by a mechanism other than regulation of ROS activity.

                Author and article information

                Am J Nephrol
                American Journal of Nephrology
                S. Karger AG
                October 2004
                01 December 2004
                : 24
                : 5
                : 497-502
                aPediatric Nephrology Unit, Karolinska University Hospital-Huddinge, bDepartment of Laboratory Medicine, Division of Pathology, and cNational Institute of Environmental Medicine, Division of Toxicology and Neurotoxicology, Karolinska Institutet, Stockholm, Sweden
                80726 Am J Nephrol 2004;24:497–502
                © 2004 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: 3, References: 27, Pages: 6
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/80726
                Original Report: Laboratory Investigation

                Cardiovascular Medicine, Nephrology

                Kidney development, Apoptosis, Dexamethasone


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