Protein responses in cadmium toxicity of renal epithelia

镉是一种重要的工业和环境毒素，引起众所周知的人类健康问题。 大多数人长期暴露于低浓度的镉，这种暴露的最重要目标是肾小管上皮细胞（RTEs）。 镉暴露改变暴露的RTEs的细胞骨架调节，有限的数据表明，镉诱导的蛋白质，包括热休克蛋白27，已知调节肌动蛋白丝组装的应激反应蛋白的表达或调节的变化。 很少有研究专门探讨热休克蛋白27的调节或功能，在长期低水平镉暴露，无论是精确的方式，也没有改变热休克蛋白27的表达和调节的意义，在RTEs很好地理解。 在初步研究中，我们发现，低剂量的镉在几天内诱导肌动蛋白组织的改变，并观察伴随的非磷酸化热休克蛋白27的表达增加。 我们还提供了第一个直接分析的肌动蛋白分布动力学在生活中，镉处理的RTEs，揭示镉诱导肌动蛋白丝结构的动态调节不明显从静态图像的显着变化。 由于在我们的研究中观察到的热休克蛋白27功能的变化已与减少肌动蛋白丝组装或稳定在其他系统中，我们假设，慢性镉暴露可以改变肌动蛋白丝的稳定性，并导致随之而来的变化，肌动蛋白组织在RTEs作为一个直接的后果增加热休克蛋白27的表达和细胞骨架协会。 此外，虽然hsp27已被证明可以保护单个细胞免受损伤，但许多研究表明，改变的hsp27表达和磷酸化伴随或诱导细胞分化的变化。 细胞结构和功能的变化作为改变肌动蛋白调节的结果也有很好的记录。因此，我们还假设，增加热休克蛋白27表达的RTEs长期暴露于镉，虽然提高单个细胞的存活率，改变细胞结构和行为，最终导致组织和器官功能的丧失。 本实验旨在验证这些假说，并明确热休克蛋白27在慢性镉致肾小管上皮细胞损伤中的作用。 这些研究也有望为镉诱导细胞损伤的分子机制提供新的数据，并有可能提出新的方法来治疗或预防镉和类似毒物诱导的肾损伤。

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.