PHYSICO-CHEMICAL ASPECTS OF RENAL TRANSPORT PROCESSES

正常的肾小球毛细血管壁对水具有极强的渗透性。 但在防止血浆蛋白流失到 肾小球超滤液。在肾脏疾病的主要形式中， 肾小球功能的这些方面往往会受到损害： 水过滤能力降低，伴随而来的是水过滤能力降低 选择性地保留血浆蛋白。实验中的清除研究 使用各种外源聚合物的动物和人类已经证实 肾小球屏障对大分子的选择性是基于 分子大小和分子电荷，但生物物理基础 对正常或受损的选择性仍知之甚少。具体来说， 目前可用来解释这种数据的数学模型提供了 对肾小球毛细血管的结构变化知之甚少 WALL可能会影响其作为超滤膜的性能。这个 拟议研究的总体目标是发展新的理论 模型将关联的大小和电荷的选择性质 肾小球屏障的特殊物理特性 毛细管壁内的结构。一个特别的目标是合成 并对一种新的阴离子测试大分子Ficoll硫酸盐进行了表征 作为肾小球电荷选择性的探针。第二个目标是研究 不同大小和电荷的大分子的对流和扩散 具有良好特性的合成凝胶，将用于实验 肾小球基底膜转运模型。体能 在这些研究中建立的关系将有助于实现这一目标 第三个特定目标是分析过滤和扩散数据 中性Ficoll和Ficoll硫酸盐对大鼠肾小球的影响 基底膜。合成凝胶和基底膜都会 将其模拟为通过充满流体的空隙进行传输的介质 在无序的纤维阵列中，以及对分子的限制 不同的大小和电荷将被解释为物理 光纤半径、光纤电荷和平均光纤间距等参数 间距。作为最终的主要目标，建立一个大分子的理论模型 通过完整的肾小球毛细血管壁的运输将被开发， 基于由单个上皮细胞组成的重复结构单元 滤过缝隙及相应的基底膜面积和 有窗孔的内皮细胞。这个模型将被用来阐明 不同个体结构对肾小球的贡献 在健康和疾病中观察到的渗透性特性。

The normal glomerular capillary wall is extremely permeable to water, and yet very effective at preventing the loss of plasma proteins into the glomerular ultrafiltrate. In the principal forms of kidney disease both of these aspects of glomerular function tend to be impaired: there is a reduced capacity for filtration of water, accompanied by less ability to selectively retain plasma proteins. Clearance studies in experimental animals and humans using various exogenous polymers have established that the selectivity of the glomerular barrier to macromolecules is based on both molecular size and molecular charge, but the biophysical basis for normal or impaired selectivity remains poorly understood. Specifically, the mathematical models currently available to interpret such data offer little insight into how structural changes in the glomerular-capillary wall might affect its performance as an ultrafiltration membrane. The overall objective of the proposed research is to develop new theoretical models which will relate the size- and charge-selective properties of the glomerular barrier to the physical characteristics of particular structures within the capillary wall. One specific aim is to synthesize and characterize a new anionic test macromolecule, Ficoll sulfate, for use as a probe of glomerular charge-selectivity. A second aim is to study convection and diffusion of macromolecules of varying size and charge in well-characterized synthetic gels, which will be used as experimental models for transport in the glomerular basement membrane. The physical relationships established in those studies will assist in the achievement of a third specific aim, which is to analyze filtration and diffusion data obtained with neutral Ficoll and Ficoll sulfate in isolated rat glomerular basement membrane. The synthetic gels and the basement membrane will both be modeled as media where transport is through fluid-filled interstices among a disordered array of fibers, and the restrictions to molecules of varying size and charge will be interpreted in terms of physical parameters such as fiber radius, fiber charge, and average interfiber spacing. As the final major aim, a theoretical model for macromolecule transport across the intact glomerular capillary wall will be developed, based on a repeating structural unit consisting of a single epithelial filtration slit and corresponding areas of basement membrane and fenestrated endothelium. This model will be used to elucidate the contributions of the various individual structures to glomerular permeability properties observed in health and disease.