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      Tight Junction Proteins and Oxidative Stress in Heavy Metals-Induced Nephrotoxicity

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          Abstract

          Kidney is a target organ for heavy metals. They accumulate in several segments of the nephron and cause profound alterations in morphology and function. Acute intoxication frequently causes acute renal failure. The effects of chronic exposure have not been fully disclosed. In recent years increasing awareness of the consequences of their presence in the kidney has evolved. In this review we focus on the alterations induced by heavy metals on the intercellular junctions of the kidney. We describe that in addition to the proximal tubule, which has been recognized as the main site of accumulation and injury, other segments of the nephron, such as glomeruli, vessels, and distal nephron, show also deleterious effects. We also emphasize the participation of oxidative stress as a relevant component of the renal damage induced by heavy metals and the beneficial effect that some antioxidant drugs, such as vitamin A (all-trans-retinoic acid) and vitamin E ( α -tocopherol), depict on the morphological and functional alterations induced by heavy metals.

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          Most cited references109

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          Free Radicals in Biology and Medicine

          Free Radicals in Biology and Medicine has become a classic text in the field of free radical and antioxidant research since its first publication in 1985. <br> This latest edition has been comprehensively rewritten and updated (over 80% of the text is new), while maintaining the clarity of its predecessor. There is expanded coverage of isoprostanes and related compounds, mechanisms of oxidative damage to DNA and proteins (and the repair of such damage), the free radical theory of aging and the roles played by reactive species in signal transduction, cell death, human reproduction, and other important biological events. Greater emphasis has also been placed on the methods available to measure reactive species and oxidative damage (and their potential pitfalls), as well as the importance of antioxidants in the human diet. <br> This book is recommended as a comprehensive introduction to the field for students, clinicians and researchers, and an invaluable companion to all those interested in the role of free radicals in the life and biomedical sciences.
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            Structure and function of claudins.

            Claudins are tetraspan transmembrane proteins of tight junctions. They determine the barrier properties of this type of cell-cell contact existing between the plasma membranes of two neighbouring cells, such as occurring in endothelia or epithelia. Claudins can completely tighten the paracellular cleft for solutes, and they can form paracellular ion pores. It is assumed that the extracellular loops specify these claudin functions. It is hypothesised that the larger first extracellular loop is critical for determining the paracellular tightness and the selective ion permeability. The shorter second extracellular loop may cause narrowing of the paracellular cleft and have a holding function between the opposing cell membranes. Sequence analysis of claudins has led to differentiation into two groups, designated as classic claudins (1-10, 14, 15, 17, 19) and non-classic claudins (11-13, 16, 18, 20-24), according to their degree of sequence similarity. This is also reflected in the derived sequence-structure function relationships for extracellular loops 1 and 2. The concepts evolved from these findings and first tentative molecular models for homophilic interactions may explain the different functional contribution of the two extracellular loops at tight junctions.
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              Claudin-2 expression induces cation-selective channels in tight junctions of epithelial cells.

              Tight junctions seal the paracellular pathway of epithelia but, in leaky tissues, also exhibit specific permeability. In order to characterize the contribution of claudin-2 to barrier and permeability properties of the tight junction in detail, we studied two strains of Madin-Darby canine kidney cells (MDCK-C7 and MDCK-C11) with different tight junctional permeabilities. Monolayers of C7 cells exhibited a high transepithelial resistance (>1 kOhms cm(2)), compared with C11 cells (<100 Ohms cm(2)). Genuine expression of claudin-1 and claudin-2, but not of occludin or claudin-3, was reciprocal to transepithelial resistance. However, confocal microscopy revealed a marked subjunctional localization of claudin-1 in C11 cells, indicating that claudin-1 is not functionally related to the low tight junctional resistance of C11 cells. Strain MDCK-C7, which endogenously does not express junctional claudin-2, was transfected with claudin-2 cDNA. In transfected cells, but not in vector controls, the protein was detected in colocalization with junctional occludin by means of immunohistochemical analyses. Overexpression of claudin-2 in the originally tight epithelium with claudin-2 cDNA resulted in a 5.6-fold higher paracellular conductivity and relative ion permeabilities of Na(+) identical with 1, K(+)=1.02, NMDG(+)=0.79, choline(+)=0.71, Cl(-)=0.12, Br(-)=0.10 (vector control, 1:1.04:0.95:0.94:0.85:0.83). By contrast, fluxes of (radioactively labeled) mannitol and lactulose and (fluorescence labeled) 4 kDa dextran were not changed. Hence, with regular Ringer's, Na(+) conductivity was 0.2 mS cm(-2) in vector controls and 1.7 mS cm(-2) in claudin-2-transfected cells, while Cl(-) conductivity was 0.2 mS cm(-2) in both cells. Thus, presence of junctional claudin-2 causes the formation of cation-selective channels sufficient to transform a 'tight' tight junction into a leaky one.
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                Author and article information

                Journal
                Biomed Res Int
                Biomed Res Int
                BMRI
                BioMed Research International
                Hindawi Publishing Corporation
                2314-6133
                2314-6141
                2013
                22 April 2013
                : 2013
                : 730789
                Affiliations
                Physiology, Biophysics and Neurosciences Department, Center for Research and Advanced Studies, National Polytechnic Institute, Avenida Instituto Politécnico Nacional 2508, Colonia San Pedro Zacatenco, 07360 Mexico, DF, Mexico
                Author notes

                Academic Editor: Cheng-An J. Lin

                Article
                10.1155/2013/730789
                3654622
                23710457
                0835c06d-7020-4339-8d04-0976b660056c
                Copyright © 2013 José L. Reyes et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 20 December 2012
                : 27 March 2013
                Categories
                Review Article

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