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AMINOGLYCOSIDE NEPHROTOXICITY AND CELLULAR TRANSPORT

氨基糖苷肾毒性和细胞转运

基本信息

批准号：
3302098
负责人：
MARY ANN SENS
金额：
$ 11.53万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
1990
资助国家：
美国
起止时间：
1990-03-01 至 1994-02-28
项目状态：
已结题

项目摘要

The aminoglycoside antibiotics are extremely useful in the treatment of gram-negative sepsis, and their clinical utility is associated with dose- limiting nephrotoxicity. The studies to be performed will employ a cell culture model of the human proximal tubule to determine the cellular basis of aminoglycoside-induced nephrotoxicity. The studies proposed will test the hypothesis that the nephrotoxicity of the aminoglycoside antibiotics results from a failure of the proximal tubule cell to maintain ion homeostasis. Central to this hypothesis is an aminoglycoside-induced alteration in proximal tubule sodium-dependent transport processes. It is well known that the degree on the polarization and differentiation of the epithelial cell. It is proposed that highly-differentiated proximal tubule cells are dependent of these sodium-dependent processes and susceptible to aminoglycoside-induced alteration in these processes. However, upon aminoglycoside-induced necrosis, these highly-differentiated cells are replaced by more primitive epithelial cells that are not yet polarized. It is postulated that these cells are not reliant on sodium-dependent processes and, thus, are resistant to the aminoglycosides. Preliminary data is presented to support this hypothesis. Of central significance is the fact that this hypothesis would explain the well-known observation that aminoglycoside-induced nephrotoxicity and cell regeneration occur as a simultaneous event in the clinical and animal model settings. This hypothesis would be supported by completion of specific aims designed to demonstrate: 1. a general alteration in sodium-dependent transport processes as a function of aminoglycoside exposure, 2. an increased aminoglycoside toxicity when cells are exposed to agents which increase sodium-dependent transport processes, and 3. aminoglycoside-induced alterations in the electrical and structural properties of the cell membrane that are consistent with an alteration in sodium-dependent transport processes.

氨基糖苷类抗生素对于治疗以下疾病非常有用革兰氏阴性脓毒症，其临床效用与剂量相关限制肾毒性。要进行的研究将使用细胞人类近曲小管培养模型以确定细胞基础氨基糖苷类药物引起的肾毒性。拟议的研究将测试氨基糖苷类抗生素的肾毒性假设近端小管细胞无法维持离子的结果体内平衡。该假说的核心是氨基糖苷类药物诱导的近曲小管钠依赖性转运过程的改变。这是众所周知，极化和分化的程度上皮细胞。近端小管高度分化细胞依赖于这些钠依赖性过程并且容易受到氨基糖苷类药物诱导这些过程的改变。然而，基于氨基糖甙类药物引起的坏死，这些高度分化的细胞被尚未极化的更原始的上皮细胞所取代。它假设这些细胞不依赖于钠依赖性过程，因此对氨基糖苷类药物具有抗性。初步的提供数据来支持这一假设。最重要的是事实上，这个假设可以解释众所周知的观察结果氨基糖苷类诱导的肾毒性和细胞再生作为临床和动物模型设置中的同时事件。这假设将通过完成旨在实现的具体目标来支持证明： 1. 钠依赖性转运的总体改变过程作为氨基糖苷类暴露的函数，2.增加当细胞暴露于会增加氨基糖苷类毒性的物质时钠依赖性转运过程，以及 3. 氨基糖苷类诱导的细胞电学和结构特性的改变膜与钠依赖性的改变一致运输过程。