CADMIUM, ZINC, METALLOTHIONEIN AND KIDNEY TOXICITY

镉暴露是人体毒理学中的一个重要问题。一个 中毒的主要部位是肾脏，镉导致中度肾脏。 失败包括不能吸收营养物质，如葡萄糖，磷酸盐， 钙和氨基酸。在小鼠肾皮质细胞中，它类似于 近端小管细胞，不影响细胞的镉浓度 活性、ATP水平或(Na+，K+)-ATPase活性抑制 (Na+)依赖的葡萄糖和磷酸盐的共同运输。显然，镉离子 直接作用于转运体生物化学，而不是间接地通过干扰 节能机制。事实上，镉离子下调了 (Na+)-葡萄糖(SGLT1)和(Na+)-磷酸共转运体mRNA。它也一直是 发现镉离子的主要结合部位金属硫蛋白(MT)， 不能逆转镉离子对SGLT1的抑制作用 蛋白质结合的镉离子的有效清除剂。要了解这些机制， 下调(Na+)营养依赖的协同转运体参与 镉离子肾毒性及其与金属硫蛋白诱导的关系 和活性作为一种有效的金属结合剂，以下具体目标将 研究方向：1)明确镉离子对SGLT1hnRNA和mRNA的影响。2) 测定对照和对照SGLT1 mRNA降解的速率常数 镉处理过的细胞。3)检测镉离子对SGLT1蛋白的影响 降解和合成。4)建立镉与环境的关系 离子依赖性抑制SGLT1活性和减少SGLT1基因表达。5) SGLT1基因表达下调的机制探讨 浓度抑制SGLT1启动子驱动的荧光素酶表达。6) 开发一种体内模型，可用于评估IN的意义 体外机制研究。7)开展镉离子效应研究 关于(Na+)-磷酸共转运的平行目标1-6。8)建立 镉、锌离子诱导MT基因合成的机制。9) 从细胞水平检测SGLT1基因表达下调的机制 化学透视法。10)探索MT之间的金属离子交换竞争 以及其他与镉离子相互作用的关键分子。

Cadmium exposure is an important problem in human toxicology. A major site of toxicity is the kidney where cadmium causes moderate renal failure including an inability to resorb nutrients such as glucose, phosphate, calcium, and amino acids. In mouse kidney cortical cells, which resemble proximal tubule cells, concentrations of cadmium, which do not affect cell viability, ATP levels, or the activity of the (Na+, K+)-ATPase, inhibit (Na+)-dependent glucose and phosphate co-transport. The cadmium ion apparently acts directly on transporter biochemistry not indirectly through disruption of energy conservation mechanisms. Indeed, cadmium ion down regulates (Na+)-glucose (SGLT1) and (Na+)-phosphate co-transporter mRNA. It has also been found that metallothionein (MT), the principal site of binding of cadmium ion, does not reverse inhibition of SGLT1 by cadmium ion even though it is an effective scavenger for protein-bound cadmium ion. To understand the mechanisms of down regulation of (Na+)-nutrient dependent co transporters involved in cadmium ion nephrotoxicity and their relationship to metallothionein induction and activity as a potent metal binding agent, the following specific aims will be pursued: 1) Define the effects of cadmium ion on SGLT1 hnRNA and mRNA. 2) Determine the rate constants for degradation of SGLT1 mRNA from control and cadmium treated cells. 3) Measure the impact of cadmium ion on SGLT1 protein degradation and synthesis. 4) Establish the relationship between cadmium ion-dependent inhibition of SGLT1 activity and reduction in SGLT1 mRNA. 5) Investigate the mechanism of down-regulation of SGLT1 mRNA concentration-inhibition of SGLT1 promoter-driven luciferase expression. 6) Develop an in vivo model that can be used to assess the significance of the in vitro mechanistic studies. 7) Carry out studies on the effects of cadmium ion on (Na+)-phosphate co transport that parallel aims 1-6. 8) Establish the mechanism of induction of MT mRNA synthesis by cadmium ion and zinc ion. 9) Examine the mechanism of down-regulation of SGLT1 mRNA concentration from a chemical perspective. 10) Probe the metal ion exchange competition between MT and other key molecules interacting with cadmium ion.