CELLULAR BASIS OF NEPHROTOXICITY

肾毒性的细胞基础

• 批准号: 3876247
• 负责人: STEVEN R GULLANS
• 金额: --
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3876247
• 关键词: acid base balance; acute renal failure; adenosine triphosphate; calcium flux; cellular pathology; cis platinum compound; cyclosporines; drug adverse effect; gentamicins; ion transport; kidney circulation; kidney metabolism; laboratory rabbit; magnesium; magnetic resonance imaging; mitochondria; nuclear magnetic resonance spectroscopy; pharmacokinetics; renal toxin; renal tubule

Drug-related nephrotoxicity is a major cause of renal failure and limits the use of clinically important agents such as cisplatin, gentamicin, and cyclosporine. Unfortunately, the cellular basis of these cytotoxic actions is poorly understood. The present investigation will use a combination of in vitro and in vivo approaches to dissociate direct from indirect tubular effects and to identify specific physiological processes which are adversely affected by these three drugs. Five issues will be addressed: 1) By isolating proximal tubules, medullary thick ascending limbs (mTAL), and inner medullary collecting ducts (IMCD), we will identify nephron segments which are injured. Acute and chronic studies will evaluate the effects of direct drug additions to suspended cells as well as the physiological status of cells isolated from animals receiving in vivo treatment. 2) Ion-specific electrodes (K+ and Ca2+), an oxygen electrode, and biochemical assays will uncover drug-induced alterations in ion transport, cellular Ca2+ regulation, mitochondrial ATP production, and other cellular processes. 3) Using magnetic resonance spectroscopy (MRS) we will identify metabolites of these drugs and resolve their role in mediating toxicity. 4) By using in vivo magnetic nephrotoxin- mediated changes in renal metabolism and renal blood flow will be observed non-invasively. 31P MRS will be used to monitor in vivo changes in renal ATP, pH, and Mg2+. Furthermore, new magnetic resonance imaging (MRI) techniques will be used to image in vivo differences in regional fluid flow. These flow sensitive techniques can selectively highlight flow in large blood vessels or microcirculation. 5) With this knowledge of nephrotoxin-induced changes in renal function, therapies to reduce or prevent nephrotoxicity will be designed and investigated. Overall, these strategies offer an experimentally sound approach to identifying the basis of cytotoxic injury associated with these nephrotoxins.

与药物有关的肾毒性是肾衰竭和 限制使用临床上重要的药物，例如顺铂， 庆大霉素和环孢菌素。 不幸的是，细胞基础 这些细胞毒性作用中的知识很少。 现在 调查将结合体外和体内 直接与间接管状作用分离的方法 确定特定的生理过程，这些过程是不利的 受这三种药物的影响。 将解决五个问题：1） 通过隔离近端小管，髓质厚的升节 （MTAL）和内髓质收集管（IMCD），我们将 识别受伤的肾单位段。 急性和慢性 研究将评估直接添加药物对 悬浮细胞以及细胞的生理状态 从接受体内治疗的动物中分离出来。 2）特定于离子 电极（K+和Ca2+），氧电极和生化 测定将发现药物诱导的离子转运的改变， 细胞Ca2+调节，线粒体ATP的产生和其他 细胞过程。 3）使用磁共振光谱（MRS） 我们将确定这些药物的代谢物并解决其作用 在介导毒性中。 4）使用体内磁性肾毒素 - 肾脏代谢和肾血流的介导变化将是 观察到非侵入性。 31p MRS将用于监测体内 肾脏ATP，pH和MG2+的变化。 此外，新磁性 共振成像（MRI）技术将用于体内图像 区域流体流的差异。 这些流动敏感 技术可以选择性地突出大型血管中的流动 或微循环。 5）有了肾毒素诱导的知识 肾功能的变化，减少或预防的疗法 将设计和研究肾毒性。 总体而言，这些 策略为识别实验性合理的方法提供了 与这些肾毒素相关的细胞毒性损伤的基础。