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      Nephrotoxicity and the Proximal Tubule

      a,b

      Nephron Physiology

      S. Karger AG

      Apoptosis, Metallothionein, Cytchrome <italic>c</italic>, Endocytosis, P-glycoprotein

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          Abstract

          Cadmium (Cd<sup>2+</sup>) 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<sup>2+</sup> 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<sup>2+</sup> uptake by PT cells (PTCs) in vivo is apical endocytosis of Cd<sup>2+</sup> complexed to the high-affinity metal-binding protein metallothionein (MT), which may be receptor-mediated. MT is subsequently degraded in endo-lysosomes, and Cd<sup>2+</sup> is liberated for translocation into the cytosolic compartment, possibly using transporters for Fe<sup>2+</sup>, Zn<sup>2+</sup> or Cu<sup>2+</sup>, such as the divalent metal transporter DMT1. Free Cd<sup>2+</sup> 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<sup>2+</sup> generates reactive oxygen species (ROS), which deplete endogenous radical scavengers. ROS also damage a variety of transport proteins, including the Na<sup>+</sup>/K<sup>+</sup>-ATPase, which are subsequently degraded by the proteasome and endo-lysosomal proteases. Cd<sup>2+</sup> 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<sup>2+</sup> also induces the upregulation of cytoprotective stress and metal-scavenging proteins, such as MT. In addition, Cd<sup>2+</sup> upregulates the detoxifying pump multidrug resistance P-glycoprotein, which appears to protect PTCs against Cd<sup>2+</sup>-induced apoptosis. Thus, Cd<sup>2+</sup> 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<sup>2+</sup> nephrotoxicity should provide insights into other heavy metal (e.g. Pb<sup>2+</sup>, Hg<sup>2+</sup>) nephropathies and various forms of acquired Fanconi syndrome.

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          Most cited references 6

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          Metallothionein: an intracellular protein to protect against cadmium toxicity.

          Metallothioneins (MT) are low-molecular-weight, cysteine-rich, metal-binding proteins. MT genes are readily induced by various physiologic and toxicologic stimuli. Because the cysteines in MT are absolutely conserved across species, it was suspected that the cysteines are necessary for function and MT is essential for life. In attempts to determine the function(s) of MT, studies have been performed using four different experimental paradigms: (a) animals injected with chemicals known to induce MT; (b) cells adapted to survive and grow in high concentrations of MT-inducing toxicants; (c) cells transfected with the MT gene; and (d) MT-transgenic and MT-null mice. Most often, results from studies using the first three approaches have indicated multiple functions of MT in cell biology: MT (a) is a "storehouse" for zinc, (b) is a free-radical scavenger, and (c) protects against cadmium (Cd) toxicity. However, studies using MT-transgenic and null mice have not strongly supported the first two proposed functions but strongly support its function in protecting against Cd toxicity. Repeated administration of Cd to MT-null mice results in nephrotoxicity at one tenth the dose that produces nephrotoxicity in control mice. Human studies indicate that 7% of the general population have renal dysfunction from Cd exposure. Therefore, if humans did not have MT, "normal" Cd exposure would be nephrotoxic to humans. Thus, it appears that during evolution, the ability of MT to protect against Cd toxicity might have taken a more pivotal role in the maintenance of life processes, as compared with its other proposed functions (i.e. storehouse for zinc and free radical scavenger).
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            Cadmium, gene regulation, and cellular signalling in mammalian cells.

            Effects of the carcinogenic metal cadmium on the regulation of mammalian gene expression are reviewed and discussed in the light of observations on interference with cellular signal transduction pathways. Cadmium ions are taken up through calcium channels of the plasma membrane of various cell types, and cadmium is accumulated intracellularly due to its binding to cytoplasmic and nuclear material. At elevated cytotoxic concentrations, cadmium inhibits the biosyntheses of DNA, RNA, and protein, and it induces lipid peroxidation, DNA strand breaks, and chromosome aberrations. Cadmium compounds as such are only weak mutagens and clastogens. However, cadmium at noncytotoxic doses interferes with DNA repair processes and enhances the genotoxicity of directly acting mutagens. Hence, the inhibition of repair and detoxifying enzymes by this metal may partially explain the observed weak genotoxic properties of this metal. Nongenotoxic mechanisms upregulating intracellular signalling pathways leading to increased mitogenesis are discussed as major mechanisms for the interpretation of the carcinogenic activity by chronic cadmium exposure. About 1 microM cadmium stimulates DNA synthesis and cell proliferation in various cell lines, whereas more elevated concentrations are inhibitory. Cadmium enhances the expression of several classes of genes at concentrations of a few microM. It stimulates the expression of immediate early genes (c-fos, c-jun, and c-myc), of the tumor suppressor gene p53, and of genes coding for the syntheses of protective molecules, including metallothioneins, glutathione, and stress (heat shock) proteins. The mechanisms underlying the modulation of gene activity by cadmium are discussed in terms of interference with cellular signalling at the levels of cell surface receptors, cellular calcium and zinc homeostases, protein phosphorylation, and modification of transcription factors. In considering the available evidence, the carcinogenic properties of cadmium are interpreted using a multifactorial approach involving indirect genotoxicity (interference with DNA repair) and the upregulation of mitogenic signalling pathways.
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              Up-regulation of multidrug resistance P-glycoprotein via nuclear factor-kappaB activation protects kidney proximal tubule cells from cadmium- and reactive oxygen species-induced apoptosis.

              Cadmium-mediated toxicity of cultured proximal tubule (PT) cells is associated with increased production of reactive oxygen species (ROS) and apoptosis. We found that cadmium-dependent apoptosis (Hoechst 33342 and annexin V assays) decreased with prolonged CdCl(2) (10 microM) application (controls: 2.4 +/- 1.6%; 5 h: +5.1 +/- 2.3%, 20 h: +5.7 +/- 2.5%, 48 h: +3.3 +/- 1.0% and 72 h: +2.1 +/- 0.4% above controls), while cell proliferation was not affected. Reduction of apoptosis correlated with a time-dependent up-regulation of the drug efflux pump multidrug resistance P-glycoprotein (mdr1) in cadmium-treated cells ( approximately 4-fold after 72 h), as determined by immunoblotting with the monoclonal antibody C219 and measurement of intracellular accumulation of the fluorescent probe calcein +/- the mdr1 inhibitor PSC833 (0.5 microM). When mdr1 inhibitors (PSC833, cyclosporine A, verapamil) were transiently added to cells with mdr1 up-regulation by pretreatment for 72 h with cadmium, cadmium-induced apoptosis increased significantly and to a percentage similar to that obtained in cells with no mdr1 up-regulation (72-h cadmium: 5.2 +/- 0.9% versus 72-h cadmium + 1-h PSC833: 7.2 +/- 1.4%; p < or = 0.001). Cadmium-induced apoptosis and mdr1 up-regulation depended on ROS, since co-incubation with the ROS scavengers N-acetylcysteine (15 mM) or pyrrolidine dithiocarbamate (0.1 mM) abolished both responses. Moreover, cadmium- and ROS-associated mdr1 up-regulation was linked to activation of the transcription factor NF-kappaB; N-acetylcysteine, pyrrolidine dithiocarbamate, and the IkappaB-alpha kinase inhibitor Bay 11-7082 (20 microM) prevented both, mdr1 overexpression and degradation of the inhibitory NF-kappaB subunit, IkappaB-alpha, induced by cadmium. The data show that 1) cadmium-mediated apoptosis in PT cells is associated with ROS production, 2) ROS increase mdr1 expression by a process involving NF-kappaB activation, and 3) mdr1 overexpression protects PT cells against cadmium-mediated apoptosis. These data suggest that mdr1 up-regulation, at least in part, provides anti-apoptotic protection for PT cells against cadmium-mediated stress.
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                Author and article information

                Journal
                NEP
                Nephron Physiol
                10.1159/issn.1660-2137
                Nephron Physiology
                S. Karger AG
                1660-2137
                2003
                April 2003
                09 May 2003
                : 93
                : 4
                : p87-p93
                Affiliations
                aSchool of Biological Sciences, University of Manchester, Manchester, UK; bDepartment of Physiology and Pathophysiology, University of Witten/Herdecke, Witten, Germany
                Article
                70241 Nephron Physiol 2003;93:p87–p93
                10.1159/000070241
                12759569
                © 2003 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: 16, Pages: 1
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                Self URI (application/pdf): https://www.karger.com/Article/Pdf/70241
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