Proximal Tubule Albumin Transport in Disease States

描述(由申请人提供)：虽然蛋白尿，特别是蛋白尿的临床相关性已经被很好地记录下来，但不同屏障成分对蛋白尿的定量机制贡献或作用仍然是一个相当令人兴奋和争论的领域。几个实验室利用不同科学方法的最新数据描绘了近端小管在白蛋白重吸收和回收中的潜在作用，它是白蛋白尿尿液屏障的另一个重要决定因素。因此，本申请建议以纵向方式解剖和量化同一大鼠在生理和疾病条件下肾小球和近端小管对蛋白尿的贡献。结构、功能和机制的观察将相互关联，以促进我们目前对这一临床重要现象的理解。我们的总体假设是，肾小球通透性和近端小管细胞都发挥着基础的、生理学的、协同的、相互作用的和可诱导的作用，试图维持生理状态，最大限度地减少蛋白尿。我们进一步假设，肾小球白蛋白通透性或近端小管白蛋白回收的急性或慢性改变可以直接影响蛋白尿。为了直接评估这一假说，我们开发了必要的技术、方法和动物模型来解剖、量化、理解和相互联系肾小球通透性的急性和慢性变化以及近端肾小管细胞重吸收和过滤白蛋白的跨细胞作用。

DESCRIPTION (provided by applicant): While the clinical relevance of proteinuria, and especially albuminuria, has been well documented the quantitative mechanistic contribution or role of different barrier components to albuminuria remains an area of considerable excitement and debate. Recent data from several laboratories utilizing different scientific approaches have delineated a potential role of proximal tubules in albumin reabsorption and reclamation as another important determinant of the urinary barrier to albuminuria. Therefore, the present application proposes to dissect apart and quantify glomerular and proximal tubule contributions to albuminuria under physiologic and disease conditions in a longitudinal fashion in the same rats. Structural, functional and mechanistic observations will be interrelated to advance our present understanding of this clinically important phenomenon. Our Overall Hypothesis is that both glomerular permeability and proximal tubule cells play fundamental, physiologic, synergistic, interactive and inducible roles to try and maintain the physiological state and minimize albuminuria. We further hypothesize that acute or chronic alterations in glomerular albumin permeability or in proximal tubule albumin reclamation can directly affect albuminuria. To directly evaluate this hypothesis we have developed the necessary techniques, approaches and animal models to dissect, quantify, understand and interrelate the role of acute and chronic changes in glomerular permeability and proximal tubular cell reabsorption and transcytosis of filtered albumin.