Cadmium is an important industrial and environmental toxin causing well known well human health problems. Most humans are exposed to cadmium at low concentrations over extended period, and the most significant target of such exposure are kidney (renal) tubular epithelial cells (RTEs). Cadmium exposure alters cytoskeletal regulation in exposed RTEs, and limited data indicate that cadmium induces changes in expression or regulation of proteins including hsp27, a stress response protein known to regulate actin filament assembly. Few studies have specifically examine dhsp27 regulation or function during extended low level cadmium exposure and neither the precise manner nor the significance of altered hsp27 expression and regulation of RTEs are well understood.. In preliminary studies, we find that low doses of cadmium over periods of several days induces alteration in actin organization and increases in hsp27 expression but not phosphorylation. We also provide the first direct analysis of actin distribution kinetics in living, cadmium treated RTEs, revealing that cadmium induces dramatic alterations in the dynamic regulation of actin filament structures not apparent from static images. Because changes in hsp27 function observed in our studies have been correlated with reduced actin filament assembly or stabilization in other systems, we hypothesize that chronic cadmium exposure can alter actin filament stabilization and causes consequent changes in actin organization in RTEs as a direct consequence of increased hsp27 expression and cytoskeletal association. Additionally, although hsp27 may protect cells against injury by stabilizing actin, numerous studies make clear that altered hsp27 expression and changes in phosphorylation accompany or inducer changes in cell differentiation. Changes in cell structure and function as a consequence of altered actin regulation are also well documented. Thus, we also hypothesize that increases of hsp27 expression in RTEs chronically exposed to cadmium, although perhaps enhancing individual cell survival cell survival,, alters cell structure and behavior leading to eventual loss of tissue and organ function. Experiments proposed here will test these hypothesis and will define the role of hsp27 in chronic cadmium induced injury and have the potential to suggest novel approaches to the treatment of prevention of renal injury induced by cadmium and similar toxicants.
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