GLOMERULAR HYPERTENSION AND SIEVING OF MACROMOLECULES

肾小球毛细血管性高血压似乎在肾性高血压中起重要作用。 肾脏疾病的进展。 平均肾小球 跨膜压差（<deltaP>）与 蛋白尿和肾小球硬化的发展，在各种 进行性肾病的实验模型，以及 <deltaP>在大鼠中已显示出提供结构保护， 保持过滤能力和选择性。 第一个目标 拟议的研究是阐明潜在的物理因素， 对<deltaP>屏障功能的影响，包括肾小球 孔径分布和膜固定电荷。 第二个目标是 开发和验证使用外源示踪剂清除的方法 大分子来估计<deltaP>。 右旋糖酐清除率分数， 聚蔗糖和硫酸葡聚糖将在正常大鼠和大鼠中测量 各种形式的肾小球损伤，慢性或急性 的变化<deltaP>。 肾小球微穿刺测量 相同动物的血流动力学变量将允许精确的 表征压力引起的膜性能变化，以及 将允许直接与<deltaP>使用 葡聚糖筛分数据。 将开发理论模型， 对葡聚糖探针和肾小球的更真实的描述 比目前的障碍。 将这些模型应用于 微穿刺和清除数据将使评估 第一次的相对贡献的大小和电荷相关的缺陷， 伴随肾小球高血压的蛋白尿。 使用这些 模型来定义从葡聚糖计算的最佳方法<deltaP> 筛选大鼠的数据将有助于实现长期目标（超越 本建议的范围）开发一种非侵入性方法， 在<deltaP>人类中进行估计，目前还没有方法 监测疾病或治疗对……的影响<deltaP>。

Glomerular capillary hypertension appears to play an important role in the progression of renal disease. Elevations in the mean glomerular transmembrane pressure difference (<deltaP>) are associated with the development of proteinuria and glomerular sclerosis in a variety of experimental models of progressive renal disease, and normalization of <deltaP> in rats has been shown to provide structural protection and to preserve filtration capacity and selectivity. The first aim of the proposed research is to elucidate the physical factors underlying the effects of <deltaP> on barrier function, including changes in glomerular pore-size distribution and membrane fixed charge. The second aim is to develop and verify methods for using the clearances of exogenous tracer macromolecules to estimate <deltaP>. Fractional clearances of dextran, ficoll, and dextran sulfate will be measured in normal rats and in rats with various forms of glomerular injury, following chronic or acute alterations in <deltaP>. Micropuncture measurements of glomerular hemodynamic variables in the same animals will permit the precise characterization of pressure-induced changes in membrane properties, and will allow a direct comparison with values of <deltaP> estimated using dextran sieving data. Theoretical models will be developed which provide more realistic descriptions of the dextran probes and of the glomerular barrier than are presently available. Application of these models to the micropuncture and clearance data will make it possible to assess for the first time the relative contributions of size-and-charge-related defects to the albuminuria that accompanies glomerular hypertension. Use of these models to define the optimal approach for calculating <deltaP> from dextran sieving data in rats will contribute to the long-term objective (beyond the scope of this proposal) of developing a noninvasive methodology for estimating <deltaP> in humans, for whom there is presently no method to monitor the effects of disease or therapy on <deltaP>.