Protein responses in cadmium toxicity of renal epithelia

镉是一种重要的工业和环境毒素，引起了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（肾）小管上皮细胞（rte）。镉暴露改变了暴露的rte的细胞骨架调节，有限的数据表明，镉诱导包括hsp27在内的蛋白质表达或调节的变化，hsp27是一种已知的调节肌动蛋白丝组装的应激反应蛋白。很少有研究专门研究hsp27在长时间低水平镉暴露期间的调节或功能，并且对rte中hsp27表达和调节改变的确切方式和意义都没有很好的了解。在初步研究中，我们发现持续数天的低剂量镉可诱导肌动蛋白组织的改变，并观察到非磷酸化hsp27的表达随之增加。我们还提供了活体镉处理rte中肌动蛋白分布动力学的第一个直接分析，揭示了镉诱导肌动蛋白丝结构的动态调节发生了巨大变化，这在静态图像中是不明显的。由于在我们的研究中观察到的hsp27功能的变化与其他系统中肌动蛋白丝组装或稳定的减少有关，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rte中肌动蛋白组织的随之变化，这是hsp27表达和细胞骨架关联增加的直接后果。此外，尽管hsp27已被证明可以保护个体细胞免受损伤，但许多研究表明，hsp27表达和磷酸化的改变伴随或诱导了细胞分化的变化。肌动蛋白调节的改变也引起了细胞结构和功能的改变。因此，我们也假设慢性暴露于镉的rte中hsp27表达的增加，虽然提高了个体细胞的存活率，但改变了细胞结构和行为，最终导致组织和器官功能的丧失。本文提出的实验将验证这些假设，并将确定hsp27在慢性镉诱导肾小管上皮细胞损伤中的作用。这些研究还有望提供有关镉诱导细胞损伤的分子机制的新数据，并有可能提出治疗或预防镉和类似毒物引起的肾损伤的新方法。

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.