AMINOGLYCOSIDE NEPHROTOXICITY AND CELLULAR TRANSPORT

氨基糖苷肾毒性和细胞转运

• 批准号: 3302094
• 负责人: MARY ANN SENS
• 金额: $ 13.71万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-03-01 至 1993-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3302094
• 关键词: adenosine triphosphate; aminoacid transport; aminoglycoside antibiotics; biological transport; cell cycle; cell membrane; cyclic AMP; epithelium; fluid; freeze etching; gentamicins; glucose transport; human tissue; inositol phosphates; ion transport; kidney necrosis; membrane potentials; neomycin; renal toxin; renal tubular transport; renal tubule; sodium potassium exchanging ATPase; streptomycin; tissue /cell culture

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.

氨基糖苷类抗生素在治疗 革兰氏阴性脓毒症，其临床效用与剂量相关， 限制肾毒性。 进行的研究将使用一个细胞， 人近端小管的培养模型，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 结果是近曲小管细胞不能维持离子 体内平衡 这一假设的核心是氨基糖苷类诱导的 近端小管钠依赖性转运过程的改变。 是 众所周知，两极分化和分化的程度， 上皮细胞 提示高分化的近曲小管 细胞依赖于这些钠依赖性过程， 氨基糖苷类药物引起的这些过程的改变。 可是 氨基糖苷类诱导的坏死，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，因此对氨基糖苷类有抗性。 初步 提供数据来支持这一假设。 最重要的是 这一假设可以解释众所周知的观察结果， 氨基糖苷类药物诱导的肾毒性和细胞再生作为一种 在临床和动物模型设置中的同时事件。 这 假设将得到具体目标的完成的支持， 演示：1. 钠依赖性转运的普遍改变 过程作为氨基糖苷类药物暴露的函数，2. 增加 当细胞暴露于增加细胞毒性的药物时， 钠依赖性运输过程，和3. 药物性 细胞的电学和结构特性的改变 膜，这与钠依赖性 运输过程。