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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Abstract

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.

Natalie D Barker (1998)

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.

Tamar Tenne, Iris Kamer, H Kalinski … (2002)

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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H Kosaka, H Matsuda, S. Shimizu … (1995)

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.

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Author and article information

Journal

Journal ID (publisher-id): AJN

Journal ID (nlm-ta): Am J Nephrol

Journal ID (doi): 10.1159/issn.0250-8095

Title: American Journal of Nephrology

Publisher: S. Karger AG

ISSN (Print): 0250-8095

ISSN (Electronic): 1421-9670

Publication date Subscription-year: 2004

Publication date (Print): October 2004

Publication date (Electronic): 01 December 2004

Volume: 24

Issue: 5

Pages: 497-502

Affiliations

^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

Article

Publisher ID: 80726 Other ID: Am J Nephrol 2004;24:497–502

DOI: 10.1159/000080726

PubMed ID: 15353912

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