The most abundant toxic metals in our environment include arsenic, cadmium, lead and mercury, and each of these metals is known to produce cellular injury to the kidney. Their toxicities are almost certainly related at least in part to the fact that urinary elimination is major route of elimination of these toxins from the body. Although the most common manifestation of this toxicity is development of tubular proteinuria associated with interstitial nephritis, significant glomerular disease can also result from toxic metal exposure. This has been most clearly demonstrated by the development of nephrotic syndrome (NS) after the use of mercury-containing compounds or occupational or environmental exposure or environmental exposure to inorganic mercury salts. However cadmium has also been reported to induce glomerular disease in addition to its well-known toxicity to kidney tubules. Exposure to toxic metals is known to induce a cellular stress response, including increased expression and phosphorylation of the small heat shock protein, hsp27, a known regulator of actin polymerization. We thus hypothesize that this regulation of actin filament by hsp27 in podocytes is mediated through a novel mechanism involving hsp27-binding proteins. To test these hypotheses we will: 1) Determine if exposure to mercury, cadmium, or combinations of these alters hsp27 expression and phosphorylation in podocytes in vitro and in vivo, and whether these metals induce podocyte structural changes characteristic of NS, 2) Determine whether induced alterations in hsp27 in vitro and in vivo result in protection from toxic metal exposure and/or podocyte structural changes characteristic of podocyte dysfunction in NS, and 3) Determine the molecular basis for the interaction between hsp27 and the recently identified hsp27-binding protein, hic-5, and analyze the role of hic-5 in regulating the podocyte cytoskeletal after toxic metal exposure. The in vitro studies will include short and long term exposure of cultured """"""""differentiated"""""""" podocytes before and after specific hsp27 and hic-5 transfections to mercuric chloride, cadmium chloride and mixtures of these metals, with subsequent analyses of hsp27 transgenic mice treated with these metals. Identification of an important role of hsp27 and hic-5 transfections to mercuric chloride, cadmium chloride and mixtures of these metals, with subsequent analyses of hsp27 expression and phosphorylation and specific podocyte structural alterations. Correlative in vivo studies will involve similar analyses of normal rats and hsp27 transgenic mice with treated with these metals. Identification of an important role of hsp27 in regulating podocyte structure after toxic metal exposure would improve our understanding of the mechanism(s) by which toxic metals induce human disease and permit the development of more highly targeted therapies for toxic metal-induced for toxic metal-induced glomerular disease.
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