Determinants of vascular permeability in the kidney glomerulus
Determinants of vascular permeability in the kidney glomerulus
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DOI：
10.1074/jbc.m204806200
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发表时间：
2002-08-23
影响因子：
4.8
通讯作者：
Kalluri, R
中科院分区：
文献类型：
--
作者：
Hamano, Y;Grunkemeyer, JA;Kalluri, R
人类肾脏每天过滤70升血浆。几乎所有肾脏疾病的标志，无论是获得性的还是遗传性的，都是由于肾脏肾小球滤过单位的改变而导致血浆蛋白渗漏到尿液中。在这方面，在肾小球中表达的nephrin、podocin、α-辅肌动蛋白-4、COL 4A 3和COL 4A 5基因中的人类突变已被认为引起肾小球滤过装置的改变。然而，这些蛋白质在肾小球血管渗漏的小鼠模型中的相互关系的表达是未知的。此外，在肾小球内，主要的滤过屏障是基底膜还是上皮细胞的狭缝隔膜的中心问题仍然不明确。因此，在这项研究中，我们使用缺乏IV型胶原α 3链（肾小球基底膜的主要成分）或LMX 1B转录因子（其调节关键的肾小球IV型胶原基因COL 4A 3和COL 4A 4或nephrin的表达）的小鼠，检测了与肾小球血管渗漏有关的肾小球上皮狭缝隔膜和肾小球基底膜蛋白的定位和表达，一种肾小球上皮细胞裂孔相关蛋白。这项研究表明，减少表达的狭缝隔膜蛋白，nephrin，与损失的肾小球滤过完整性。此外，我们表明，肾小球基底膜蛋白诱导的缺陷导致一个阴险的血浆蛋白泄漏，而肾小球上皮细胞狭缝隔膜蛋白诱导的缺陷导致一个陡峭的血浆蛋白泄漏。
The human kidneys filter 70 liters of blood plasma every day. The hallmark of almost all kidney diseases, whether acquired or genetic, is the leakage of plasma proteins into the urine because of alterations in the glomerular filtration unit of the kidney. In this regard, the human mutations in nephrin, podocin, alpha-actinin-4, COL4A3, and COL4A5 genes expressed in the glomeruli have been implicated to cause alterations in glomerular filtration apparatus. Nevertheless, the expression of these proteins in relation to each other in mouse models for glomerular vascular leak is unknown. Additionally, within the glomerulus, the central question of whether the primary filtration barrier is the basement membrane or the epithelial slit diaphragm remains ambiguous. Therefore, in this study, we examined the localization and expression of glomerular epithelial slit diaphragm and glomerular basement membrane proteins implicated in glomerular vascular leak using mice deficient in either the alpha3 chain of type IV collagen, the major constituent of glomerular basement membrane, or LMX1B transcription factor, which regulates the expression of key glomerular type IV collagen genes COL4A3 and COL4A4 or nephrin, a glomerular epithelial slit diaphragm-associated protein. This study demonstrates that decreased expression of slit diaphragm protein, nephrin, correlates with a loss of glomerular filter integrity. Additionally, we demonstrate that defects induced by proteins of glomerular basement membrane lead to an insidious plasma protein leak, whereas the defects induced by proteins in the glomerular epithelia slit diaphragms lead to a precipitous plasma protein leak.