Protein responses in cadmium toxicity of renal epithelia

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Cadmium is an important industrial and environmental toxin causing well known human health problems. Most humans are exposed to cadmium at low concentrations over extended periods, 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 examined hsp27 regulation or function during extended low level cadmium exposure and neither the precise manner nor the significance of altered hsp27 expression and regulation in 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 observe concomitant increases in expression of nonphosphorylated hsp27. 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 has been shown to protect individual cells against injury, numerous studies make clear that altered hsp27 expression and phosphorylation accompany or induce 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 increased hsp27 expression in RTEs chronically exposed to cadmium, although enhancing individual 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 to renal tubule epithelial cells. These studies are also expected to provide new data on the molecular mechanisms of cadmium induced cellular injury and have the potential to suggest novel approaches to the treatment or prevention of renal injury induced by cadmium and similar toxicants.