Fissell William H, Hofmann Christina L, Ferrell Nicholas, Schnell Lisa, Dubnisheva Anna, Zydney Andrew L, Yurchenco Peter D, Roy Shuvo
Biomedical Engineering/ND20, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA.
Am J Physiol Renal Physiol. 2009 Oct;297(4):F1092-100. doi: 10.1152/ajprenal.00162.2009. Epub 2009 Jul 8.
The physiology of glomerular filtration remains mechanistically obscure despite its importance in disease. The correspondence between proteinuria and foot process effacement suggests podocytes as the locus of the filtration barrier. If so, retained macromolecules ought to accumulate at the filtration barrier, an effect called concentration polarization. Literature data indicate macromolecule concentrations decrease from subendothelial to subepithelial glomerular basement membrane (GBM), as would be expected if the GBM were itself the filter. The objective of this study was to obtain insights into the possible role of the GBM in protein retention by performing fundamental experimental and theoretical studies on the properties of three model gels. Solute partitioning and filtration through thin gels of a commercially available laminin-rich extracellular matrix, Matrigel, were measured using a polydisperse polysaccharide tracer molecule, Ficoll 70. Solute partitioning into laminin gels and lens basement membrane (LBM) were measured using Ficoll 70. A novel model of a laminin gel was numerically simulated, as well as a mixed structure-random-fiber model for LBM. Experimental partitioning was predicted by numerical simulations. Sieving coefficients through thin gels of Matrigel were size dependent and strongly flux dependent. The observed flux dependence arose from compression of the gel in response to the applied pressure. Gel compression may alter solute partitioning into extracellular matrix at physiologic pressures present in the glomerular capillary. This suggests a physical mechanism coupling podocyte structure to permeability characteristics of the GBM.
尽管肾小球滤过在疾病中具有重要意义，但其生理机制仍不清楚。蛋白尿与足突消失之间的对应关系表明足细胞是滤过屏障的所在位置。如果是这样，保留的大分子应该在滤过屏障处积聚，这种效应称为浓差极化。文献数据表明，大分子浓度从肾小球基底膜（GBM）的内皮下层到上皮下层逐渐降低，这与GBM本身就是过滤器的预期情况相符。本研究的目的是通过对三种模型凝胶的性质进行基础实验和理论研究，深入了解GBM在蛋白质保留中的可能作用。使用多分散多糖示踪分子Ficoll 70测量溶质在富含层粘连蛋白的细胞外基质Matrigel的薄凝胶中的分配和过滤情况。使用Ficoll 70测量溶质在层粘连蛋白凝胶和晶状体基底膜（LBM）中的分配情况。对层粘连蛋白凝胶的一个新模型以及LBM的混合结构-随机纤维模型进行了数值模拟。通过数值模拟预测了实验分配情况。通过Matrigel薄凝胶的筛分系数与尺寸有关，且强烈依赖通量。观察到的通量依赖性源于凝胶在施加压力下的压缩。在肾小球毛细血管中存在的生理压力下，凝胶压缩可能会改变溶质在细胞外基质中的分配。这提示了一种将足细胞结构与GBM通透性特征相耦合的物理机制。
