MODULATION OF GLOMERULAR HYDRAULIC PERMEABILITY

拟议研究的长远目标是了解 调节肾小球水力通透性的因素并最终 限制正常肾小球和肾脏疾病的肾小球滤过率。 肾小球滤过通过一条细胞外途径进行 内皮细胞窗孔，生化复杂的基底膜， 和相邻肾小球之间的特殊缝隙-孔道连接 足细胞。超滤系数，KF或LPA是下式的乘积 毛细管壁和过滤区域的水力传导性 是单肾单位滤过率的重要决定因素。 将使用分离的肾小球在体外诱导滤过，并将KF 从应用已知的滤料后的初始过滤速度估算 渐变。将进行研究，以解决以下假设。 1)Lp在成年哺乳动物肾小球中几乎恒定；Lp在 新生儿期和血管内扩容期间的肾小球 在容量耗竭和慢性肾功能衰竭时会减少。2) 新生儿期Lp升高是胎儿发育不成熟的结果 足细胞；成熟是由糖皮质激素的作用诱导的。3) 容量耗竭和扩张过程中Lp的改变是继发性 改变灌注率和压力引起的细胞变化而不是 通过血管活性物质的直接作用。4)减少了Lp跟随 肾大部切除术也是由于肾小管上皮细胞成分的改变 滤过途径而不是滤过面积的损失；正常的LP 可以通过饮食控制或其他干预措施恢复 肾小球血流参数趋于正常。5)Lp的调制方式为 上皮裂孔处滤过途径的变化；这些 改变可能被记录在病理材料中以及之后 改变足细胞体积、细胞骨架的实验操作 或细胞间连接。

The long term goal of the proposed studies is to gain understanding of the factors that modulate glomerular hydraulic permeability and ultimately limit glomerular filtration rate in normal glomeruli and in renal disease. Glomerular filtration proceeds by an extracellular pathway that traverses endothelial cell fenestrae, the biochemically complex basement membrane, and the specialized slit-pore junctions between adjacent glomerular podocytes. The ultrafiltration coefficient, Kf or LpA, is the product of the hydraulic conductivity of the capillary wall and the filtration area and is an important determinant of single nephron filtration rate. Filtration will be induced in vitro using isolated glomeruli and Kf will be estimated from the initial rate of filtration after application of a known gradient. Studies will be conducted to address the following hypotheses. 1) Lp is nearly constant in adult mammalian glomeruli; Lp is higher in glomeruli in the neonatal period and during intravascular volume expansion and is diminished during volume depletion and in chronic renal failure. 2) Elevated Lp in the neonatal period is consequent to immaturity of podocytes; maturation is induced by the effects of glucocorticoids. 3) Altered Lp during volume depletion and expansion is the result of secondary cellular changes caused by altered perfusion rate and pressure rather than by direct effects of vasoactive substances. 4) Diminished Lp following subtotal nephrectomy also results from changes in the cellular component of the filtration pathway rather than from loss of filtering area; normal Lp may be restored by dietary manipulations or other interventions that return glomerular perfusion parameters toward normal. 5) Lp is modulated by changes in the filtration pathway at the epithelial slit-pore; these alterations may be documented in pathologic material as well as after experimental manipulations that change podocyte cell volume, cytoskeleton or intercellular junctions.