AMINOGLYCOSIDE NEPHROTOXICITY AND CELLULAR TRANSPORT

氨基糖苷类抗生素在治疗红斑狼疮方面非常有用 革兰氏阴性脓毒症，其临床疗效与剂量有关- 限制肾毒性。将要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其细胞基础 氨基糖苷类药物引起的肾毒性。拟议中的研究将检验 氨基糖苷类抗生素肾毒性的假说 近端小管细胞维持离子失败的结果 动态平衡。这一假说的核心是氨基糖苷类药物诱导的 近端小管钠依赖转运过程的改变。它是 众所周知，关于极化和分化的程度 上皮细胞。有研究认为，高分化的近端小管 细胞依赖于这些钠依赖的过程，并容易 氨基糖苷类药物可引起这些过程的改变。然而，一旦 氨基糖苷类诱导的坏死，这些高度分化的细胞 取而代之的是尚未极化的更原始的上皮细胞。它 推测这些细胞不依赖于钠依赖 因此，对氨基糖苷类具有抵抗力。初步 提供的数据支持这一假设。最重要的是 这一假设将解释众所周知的观察结果，即 氨基糖苷类药物引起的肾毒性和细胞再生表现为 临床和动物模型设置中的同步事件。这 假设将通过完成特定目标来支持，该目标旨在 证明：1.钠依赖转运的普遍改变 过程作为氨基糖苷类接触的函数，2.增加 氨基糖苷类药物对细胞的毒性作用 钠依赖的转运过程；3.氨基糖苷类药物诱导 电池的电学和结构特性的改变 与钠依赖的改变相一致的膜 运输过程。

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.