Smithies Oliver
Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599-7525, USA.
Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4108-13. doi: 10.1073/pnas.0730776100. Epub 2003 Mar 24.
Current interpretations of kidney function in terms of a coarse filter followed by a fine filter have difficulty explaining why the glomerulus does not clog. I propose, as an alternative, a semiquantitative hypothesis that assumes that the size-selective property of the glomerulus is a consequence of the limited fraction of space in the glomerular basement membrane (a concentrated gel) into which macromolecules can permeate. The glomerular epithelial cell slits and slit diaphragms are assumed to impose substantial resistance to liquid flow across the glomerulus without acting as a molecular sieve. Calculations based on gel behavior show that proteins cross the glomerular basement membrane mainly by diffusion rather than by liquid flow, whereas water crosses entirely by flow. Thus, diffusion provides most of the protein, whereas flow provides the diluent. As a result, the single-nephron glomerular filtration rate (GFR) becomes a prime factor in (inversely) determining the concentration of proteins in early proximal tubular fluid. Because the reabsorption of proteins from the tubules is a saturable process, the gel permeationdiffusion hypothesis readily accounts for the albuminuria observed when single-nephron GFR is substantially reduced by severe pathological decreases in slit diaphragm length, such as occur in minimal-change nephrotic syndrome in humans, in animals treated with puromycin aminonucleoside, or in humans or animals with mutations in the gene coding for nephrin. My hypothesis predicts that albuminuria will ensue, even with a normal kidney, if the single-nephron GFR falls below approximately 50% of normal.
目前关于肾功能的解释是先有一个粗滤器，然后是一个精滤器，但这种解释难以说明肾小球为何不会堵塞。作为一种替代方案，我提出一个半定量假说，该假说认为肾小球的大小选择性特性是肾小球基底膜（一种浓缩凝胶）中大分子能够渗透的有限空间比例的结果。肾小球上皮细胞裂孔和裂孔隔膜被认为对液体流经肾小球施加了很大阻力，但并非作为分子筛发挥作用。基于凝胶行为的计算表明，蛋白质穿过肾小球基底膜主要是通过扩散而非液体流动，而水完全是通过流动穿过。因此，扩散提供了大部分蛋白质，而流动提供了稀释剂。结果，单肾单位肾小球滤过率（GFR）成为（反向）决定近端小管早期液体中蛋白质浓度的主要因素。由于蛋白质从小管的重吸收是一个饱和过程，当单肾单位GFR因裂孔隔膜长度严重病理性减少（如人类微小病变肾病综合征、用嘌呤霉素氨基核苷治疗的动物，或编码nephrin的基因突变的人类或动物）而大幅降低时，凝胶渗透扩散假说很容易解释所观察到的蛋白尿。我的假说预测，如果单肾单位GFR降至正常的约50%以下，即使肾脏正常也会出现蛋白尿。
