CADMIUM, ZINC, METALLOTHIONEIN AND KIDNEY TOXICITY

镉暴露是人类毒理学中的一个重要问题。一 毒性的主要部位是肾脏，镉可引起中度肾毒性。 衰竭包括不能再吸收营养物如葡萄糖，磷酸盐， 钙和氨基酸。在小鼠肾皮质细胞中， 近端小管细胞，镉浓度，不影响细胞 活力、ATP水平或（Na+，K+）-ATP酶的活性抑制 (Na+）-依赖性葡萄糖和磷酸盐共转运。镉离子显然 直接作用于转运蛋白生化，而不是通过破坏 节能机制。事实上，镉离子下调 (Na+）-葡萄糖（SGLT 1）和（Na+）-磷酸盐协同转运蛋白mRNA。还已经 发现金属硫蛋白（MT），镉离子的主要结合位点， 并不逆转镉离子对SGLT 1的抑制作用， 蛋白质结合镉离子有效清除剂。为了理解这些机制 参与的（Na+）-营养依赖性协同转运蛋白的下调 镉离子肾毒性及其与金属硫蛋白诱导的关系 和作为有效的金属结合剂的活性，以下具体目的将 1）研究镉离子对SGLT 1 hnRNA和mRNA的影响。（二） 测定对照组和对照组SGLT 1 mRNA降解的速率常数， 镉处理的细胞。3)测定镉离子对SGLT 1蛋白的影响 降解和合成。4)建立镉与 SGLT 1活性的离子依赖性抑制和SGLT 1 mRNA的减少。第五章） 探讨SGLT 1 mRNA下调的机制 SGLT 1启动子驱动的荧光素酶表达的浓度抑制。六、 开发一种体内模型，可用于评估在 体外机制研究。7)开展镉离子影响的研究 对（Na+）-磷酸盐共转运的影响，平行于aims 1-6。8)建立 镉离子和锌离子诱导MT mRNA合成的机制。九、 检查从一个细胞中下调SGLT 1 mRNA浓度的机制， 化学视角10)探讨金属离子交换竞争与MT 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.