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Toxicity of the kidney proximal tubule by cadmium-metallothionein: Role of lipocalin-2 receptor-mediated endocytosis, vesicle trafficking and lysosomal DMT1

镉金属硫蛋白对肾近曲小管的毒性：脂质运载蛋白 2 受体介导的内吞作用、囊泡运输和溶酶体 DMT1 的作用

基本信息

批准号：
127488830
负责人：
Professor Dr. Frank Thévenod, Ph.D.
金额：
--
依托单位：
Lehrstuhl für Physiologie und Pathophysiologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2009
资助国家：
德国
起止时间：
2008-12-31 至 2013-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/127488830?language=en
关键词：
Toxicity kidney proximal tubule cadmium

项目摘要

Chronic exposure to the environmental contaminant cadmium (Cd) damages the kidney proximal tubule (PT). In the body Cd is bound to the protein metallothionein (MT), which is filtrated from the blood and reabsorbed by the PT to induce renal damage. In previous studies, we have shown using cultured PT cells that CdMT uptake and toxicity involves receptor-mediated endocytosis (RME), which is partly mediated by megalin and cubilin. The small GTPase ARF6 regulates early endosomal trafficking of CdMT and receptor recycling to the cell surface. The divalent metal transporter DMT1 is expressed in lysosomes of PT and participates in CdMT toxicity. Using cultured PT cells and megalinor DMT1-knockout animal models in vivo, the role of an additional receptor, the lipocalin-2 receptor, will be investigated in PT cells for RME of CdMT. Furthermore, the significance of the regulatory protein ARF1 for trafficking of CdMT from endosomes to lysosomes will be studied and degradation mechanisms of the CdMT complex will be characterized. Finally, membrane processes will be determined that are responsible for DMT1-mediated Cd fluxes from lysosomes to target organelles of Cd-toxicity (particularly mitochondria). Elucidation of these mechanisms may lead to rationales and strategies for prevention and therapy of Cd-toxicity.

慢性暴露于环境污染物镉（Cd）会损害肾脏近端小管（PT）。在体内，Cd与金属硫蛋白（MT）结合，MT从血液中过滤并被PT重吸收，从而引起肾损伤。在以前的研究中，我们已经表明，使用培养的PT细胞，CdMT的吸收和毒性涉及受体介导的内吞作用（RME），这是部分介导的megalin和cubilin。小的GTd-ARF 6调节CdMT的早期内体运输和受体再循环到细胞表面。二价金属转运体DMT 1在PT的溶酶体中表达，并参与CdMT毒性。使用培养的PT细胞和megalinor DMT 1基因敲除动物模型在体内，一个额外的受体，脂质运载蛋白-2受体的作用，将研究在PT细胞的镉的RME。此外，将研究调节蛋白ARF 1对CdMT从内体到溶酶体的运输的意义，并表征CdMT复合物的降解机制。最后，膜过程将被确定为负责DMT 1介导的镉通量从溶酶体到目标细胞器的镉毒性（特别是线粒体）。阐明这些机制可能会导致镉中毒的预防和治疗的原理和策略。