Vol. 52, Issue 1, 113-144, March 2000

Molecular Interactions with Mercury in the Kidney

Rudolfs K. Zalups¹

Division of Basic Medical Sciences, Mercer University School of Medicine, Macon, Georgia

I. Introduction
II. Renal Disposition and Transport of Mercury
    A. Intrarenal Distribution and Localization of Mercury
    B. Mechanisms of Proximal Tubular Uptake and Transport of Mercury
    C. Mechanisms of Luminal Uptake of Mercury
        1. Role of -Glutamyltransferase.
        2. Presence and Formation of Mercuric Conjugates in Proximal Tubular Lumen.
        3. Cleavage Products of Mercuric Conjugates of Glutathione as Transportable Forms of Mercury at Luminal Plasma Membrane.
        4. Role of Cysteinylglycinase.
        5. Mercuric Conjugates of Cysteine as Primary Transportable Form of Mercury at Luminal Plasma Membrane.
        6. Role of Molecular Homology.
    D. Mechanisms of Basolateral Uptake of Mercury
        1. Role of Organic Anion Transport System.
        2. Role of Dicarboxylate Transporter.
        3. Possible Ligands and Conjugates Involved in Basolateral Uptake of Mercury.
        4. Mercuric Conjugates of Glutathione as Transportable Forms of Mercury at Basolateral Membrane.
        5. Mercuric Conjugates of Cysteine as Transportable Forms of Mercury at Basolateral Membrane.
        6. Other Mercuric Conjugates as Transportable Forms of Mercury at Basolateral Membrane.
    E. Role of Liver in Renal Tubular Uptake of Mercury
    F. Intracellular Distribution of Mercury
III. Urinary Excretion of Mercury
IV. Molecular Interactions and Effects of Mercury in Renal Epithelial Cells
    A. Effects of Mercury on Intracellular Thiol Metabolism
    B. Role of Lipid Peroxidation and Oxidative Stress in Mercury-Induced Renal Cellular Injury
    C. Effects of Mercury on Renal Mitochondrial Function
    D. Effects of Mercury on Intracellular Distribution of Calcium Ions
    E. Alterations in Plasma Membrane (Na⁺+K⁺)-Stimulated ATPase Induced by Mercury
    F. Molecular Interactions between Mercuric Ions and Aquaporins (Water Channels)
    G. Influence of Mercury on Heme Metabolism
    H. Expression of Stress Proteins after Exposure to Mercury
    I. Interactions Between Mercury and Cytoskeleton
V. Renal Toxicity of Mercury
    A. Site of Tubular Injury Induced by Mercury
    B. Markers of Renal Cellular Injury and Impaired Renal Function Induced by Mercury
    C. Mercury-Induced Renal Autoimmunity
VI. Factors that Modify Renal Toxicity of Mercury
    A. Influence of Intracellular Thiols on Renal Accumulation and Toxicity of Mercury
    B. Modulation of Renal Accumulation and Toxicity of Mercury by Extracellular Thiols
    C. Effects of Reduced Nephron Number and Compensatory Tubular Hypertrophy on Renal Disposition and Toxicity of Mercury
VII. Summary
    A. Renal Accumulation and Transport of Mercury
    B. Molecular Interactions with Mercury in Renal Epithelial Cells
    C. Renal Toxicity of Mercury
    D. Factors That Influence Renal Toxicity of Mercury
Acknowledgments
References

Mercury is unique among the heavy metals in that it can exist in several physical and chemical forms, including elemental mercury, which is a liquid at room temperature. All forms of mercury have toxic effects in a number of organs, especially in the kidneys. Within the kidney, the pars recta of the proximal tubule is the most vulnerable segment of the nephron to the toxic effects of mercury. The biological and toxicological activity of mercurous and mercuric ions in the kidney can be defined largely by the molecular interactions that occur at critical nucleophilic sites in and around target cells. Because of the high bonding affinity between mercury and sulfur, there is particular interest in the interactions that occur between mercuric ions and the thiol group(s) of proteins, peptides and amino acids. Molecular interactions with sulfhydryl groups in molecules of albumin, metallothionein, glutathione, and cysteine have been implicated in mechanisms involved in the proximal tubular uptake, accumulation, transport, and toxicity of mercuric ions. In addition, the susceptibility of target cells in the kidneys to the injurious effects of mercury is modified by a number of intracellular and extracellular factors relating to several thiol-containing molecules. These very factors are the theoretical basis for most of the currently employed therapeutic strategies. This review provides an update on the current body of knowledge regarding the molecular interactions that occur between mercury and various thiol-containing molecules with respect to the mechanisms involved in the renal cellular uptake, accumulation, elimination, and toxicity of mercury.