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Protein responses in cadmium toxicity of renal epithelia

肾上皮细胞镉毒性的蛋白质反应

基本信息

批准号：
6771163
负责人：
ERIC A SHELDEN
金额：
$ 22.02万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-07-18 至 2006-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6771163
关键词：
actins cadmium cytotoxicity environmental exposure environmental toxicology epithelium laboratory mouse metal poisoning microfilaments pathologic process phosphorylation renal tubule stress stress proteins

项目摘要

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.

镉是一种重要的工业和环境毒素，会引起众所周知的人类健康问题。大多数人长期暴露在低浓度的镉中，这种暴露的最重要的目标是肾(肾)管上皮细胞(RTES)。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细丝组装的应激反应蛋白。很少有研究专门研究在长期低水平镉暴露中Hsp27的调节或功能，也没有很好地了解RTE中Hsp27表达和调节变化的确切方式和意义。在初步研究中，我们发现持续几天的低剂量镉可引起肌动蛋白组织的改变，并观察到伴随而来的非磷酸化HSP27表达的增加。我们还首次直接分析了活体、镉处理的RTE中肌动蛋白分布的动力学，揭示了镉诱导肌动蛋白细丝结构的动态调节的戏剧性变化，从静态图像上看并不明显。由于我们研究中观察到的Hsp27功能的变化与其他系统中肌动蛋白细丝组装或稳定化的减少有关，我们假设慢性镉暴露可以改变肌动蛋白细丝的稳定性，并导致RTE中肌动蛋白组织的变化，这是Hsp27表达增加和细胞骨架结合的直接结果。此外，尽管Hsp27已被证明可以保护单个细胞免受损伤，但大量研究表明，Hsp27表达和磷酸化的改变伴随或诱导了细胞分化的变化。由于肌动蛋白调控的改变，细胞结构和功能的变化也被很好地记录下来。因此，我们还假设，在长期暴露于镉的RTE中，HSP27的表达增加，尽管提高了单个细胞的存活，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说，并将确定Hsp27在慢性镉诱导的肾小管上皮细胞损伤中的作用。这些研究还有望为镉诱导细胞损伤的分子机制提供新的数据，并有可能为治疗或预防镉及类似毒物引起的肾损伤提供新的方法。