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      Zinc and Cadmium Interactions in a Renal Cell Line Derived from Rabbit Proximal Tubule

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          Abstract

          Background: The aim of this work was to characterize the relationship between zinc (Zn<sup>2+</sup>) and cadmium (Cd<sup>2+</sup>) and the toxic effects of Cd<sup>2+</sup> in immortalized renal proximal tubule cells RP1. Methods: An RP1 cell line was developed from primary cultures of microdissected S1 and S2. Uptakes of <sup>65</sup>Zn and <sup>109</sup>Cd and competitive experiments with Cd<sup>2+</sup> and Zn<sup>2+</sup> were performed and kinetic parameters were determined. Oxygen consumption, metallothionein synthesis, and necrotic and apoptotic phenomena were studied. Results: Kinetic parameters indicate that <sup>65</sup>Zn (Km = 71.8 ± 10.6 µ M) and <sup>109</sup>Cd (Km = 23.3 ± 2.0 µ M) were both transported by a saturable carrier-mediated process. Competition between Cd<sup>2+</sup> and Zn<sup>2+</sup> uptake was reciprocal. Cd<sup>2+</sup> induced an increase in necrosis and apoptosis, and a decrease in oxygen consumption, depending on Cd<sup>2+</sup> concentrations. Concomitant addition of Zn<sup>2+</sup> (10 µ M) reduced the number of necrotic and apoptotic cells and maintained oxygen consumption at control levels. Cd<sup>2+</sup> alone, or in the presence of Zn<sup>2+</sup>, increased metallothionein levels, whereas Zn<sup>2+</sup> alone did not. Conclusion: Zn<sup>2+</sup> and Cd<sup>2+</sup> probably share the same transporter in the proximal tubule. Cd<sup>2+</sup> caused necrotic and apoptotic cell death. Cd<sup>2+</sup> toxicity may occur through an effect on the mitochondrial electron transport chain and not on metallothionein synthesis. Zn<sup>2+</sup> protects against the renal cell toxicity of Cd<sup>2+</sup>.

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          Most cited references 27

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          Cadmium inhibits the electron transfer chain and induces reactive oxygen species.

          Recent research indicates that cadmium (Cd) induces oxidative damage in cells; however, the mechanism of the oxidative stress induced by this metal is unclear. We investigated the effects of Cd on the individual complexes of the electron transfer chain (ETC) and on the stimulation of reactive oxygen species (ROS) production in mitochondria. The activity of complexes II (succinate:ubiquinone oxidoreductase) and III (ubiquinol:cytochrome c oxidoreductase) of mitochondrial ETC from liver, brain, and heart showed greater inhibition by Cd than the other complexes. Cd stimulated ROS production in the mitochondria of all three tissues mentioned above. The effect of various electron donors (NADH, succinate, and 2,3-dimethoxy-5-methyl-6-decyl-1,4-benzoquinol) on ROS production was tested separately in the presence and in the absence of Cd. ESR showed that complex III might be the only site of ROS production induced by Cd. The results of kinetic studies and electron turnover experiments suggest that Cd may bind between semiubiquinone and cytochrome b566 of the Q0 site of cytochrome b of complex III, resulting in accumulation of semiubiquinones at the Q0 site. The semiubiquinones, being unstable, are prone to transfer one electron to molecular oxygen to form superoxide, providing a possible mechanism for Cd-induced generation of ROS in mitochondria.
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            Molecular handling of cadmium in transporting epithelia.

            Cadmium (Cd) is an industrial and environmental pollutant that affects adversely a number of organs in humans and other mammals, including the kidneys, liver, lungs, pancreas, testis, and placenta. The liver and kidneys, which are the primary organs involved in the elimination of systemic Cd, are especially sensitive to the toxic effects of Cd. Because Cd ions possess a high affinity for sulfhydryl groups and thiolate anions, the cellular and molecular mechanisms involved in the handling and toxicity of Cd in target organs can be defined largely by the molecular interactions that occur between Cd ions and various sulfhydryl-containing molecules that are present in both the intracellular and extracellular compartments. A great deal of scientific data have been collected over the years to better define the toxic effects of Cd in the primary target organs. Notwithstanding all of the new developments made and information gathered, it is surprising that very little is known about the cellular and molecular mechanisms involved in the uptake, retention, and elimination of Cd in target epithelial cells. Therefore, the primary purpose of this review is to summarize and put into perspective some of the more salient current findings, assertions, and hypotheses pertaining to the transport and handling of Cd in the epithelial cells of target organs. Particular attention has been placed on the molecular mechanisms involved in the absorption, retention, and secretion of Cd in small intestinal enterocytes, hepatocytes, and tubular epithelial cells lining both proximal and distal portions of the nephron. The purpose of this review is not only to provide a summary of published findings but also to provide speculations and testable hypotheses based on contemporary findings made in other areas of research, with the hope that they may promote and serve as the impetus for future investigations designed to define more precisely the cellular mechanisms involved in the transport and handling of Cd within the body.
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              Nephrotoxicity and the Proximal Tubule

              Cadmium (Cd 2+ ) is a non-essential heavy metal, which is taken up from the environment into the body through pulmonary and enteral pathways. The S1 segment of the kidney proximal tubule (PT) is a major target of chronic Cd 2+ toxicity. Renal dysfunction develops in up to 7% of the general population and in its most severe form displays major features of Fanconi syndrome, such as a defective protein, amino acid, glucose, bicarbonate and phosphate reabsorption. The major pathway for Cd 2+ uptake by PT cells (PTCs) in vivo is apical endocytosis of Cd 2+ complexed to the high-affinity metal-binding protein metallothionein (MT), which may be receptor-mediated. MT is subsequently degraded in endo-lysosomes, and Cd 2+ is liberated for translocation into the cytosolic compartment, possibly using transporters for Fe 2+ , Zn 2+ or Cu 2+ , such as the divalent metal transporter DMT1. Free Cd 2+ ions in the extracellular space are translocated across apical and/or basolateral PTC membranes into the cytosol via transporters, whose identity remains unknown. Cytosolic Cd 2+ generates reactive oxygen species (ROS), which deplete endogenous radical scavengers. ROS also damage a variety of transport proteins, including the Na + /K + -ATPase, which are subsequently degraded by the proteasome and endo-lysosomal proteases. Cd 2+ causes mitochondrial swelling and release of cytochrome c . If these ROS-mediated stress events are not balanced by repair processes, affected cells undergo apoptosis. But Cd 2+ also induces the upregulation of cytoprotective stress and metal-scavenging proteins, such as MT. In addition, Cd 2+ upregulates the detoxifying pump multidrug resistance P-glycoprotein, which appears to protect PTCs against Cd 2+ -induced apoptosis. Thus, Cd 2+ interferes with various cellular events ranging from mechanisms of induction of programmed cell death to activation of cell survival genes. A better understanding of the cellular mechanisms involved in Cd 2+ nephrotoxicity should provide insights into other heavy metal (e.g. Pb 2+ , Hg 2+ ) nephropathies and various forms of acquired Fanconi syndrome.
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                Author and article information

                Journal
                NEP
                Nephron Physiol
                10.1159/issn.1660-2137
                Nephron Physiology
                S. Karger AG
                1660-2137
                2005
                March 2005
                24 February 2005
                : 99
                : 3
                : p74-p84
                Affiliations
                Unité Mixte de Recherche, Centre National de la Recherche Scientifique 6548, Université de Nice-Sophia Antipolis, Nice, France
                Article
                83413 Nephron Physiol 2005;99:p74–p84
                10.1159/000083413
                15665557
                © 2005 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: 7, Tables: 2, References: 37, Pages: 1
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/83413
                Categories
                Original Paper

                Cardiovascular Medicine, Nephrology

                Zinc, Apoptosis, Kidney, Cadmium intoxication

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