Contribution of the endothelium to the glomerular permselectivity barrier in health and disease
Contribution of the endothelium to the glomerular permselectivity barrier in health and disease
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DOI：
10.1159/000101796
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发表时间：
2007-01-01
影响因子：
--
通讯作者：
Ballermann, Barbara J.
中科院分区：
文献类型：
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作者：
Ballermann, Barbara J.
工作背景：衬在肾小球毛细血管上的内皮与一般的内皮细胞共有许多特性，但与大多数内皮细胞不同，它非常平坦并且被跨内皮细胞孔（窗孔）密集穿孔。直到最近，人们才相信窗孔允许大蛋白质自由通过，而肾小球内皮对肾小球毛细血管壁的选择性渗透性贡献很小。方法：对肾小球毛细血管内皮细胞的性质及其对肾小球选择透过性的作用进行综述。结果如下：肾小球内皮细胞变平和窗孔形成需要来自分化的足细胞和来自肾小球基底膜的信号。足细胞VEGF-A的缺失可防止肾小球内皮的扁平化和穿孔。在体内将VEGF-A应用于内皮细胞刺激窗孔形成，并且可溶性VEGF受体1（sFlt-1）或抗VEGF抗体对VEGF-A的中和导致肾小球窗孔的丧失和蛋白尿。中和TGF-β 1抗体、小鼠层粘连蛋白α 3或人类层粘连蛋白β 3的缺失会导致类似的缺陷。先兆子痫的肾小球内皮增生病变是由于胎盘来源的抑制剂sFlt-1和sEndoglin，其分别阻断VEGF-A/VEGF受体和TGF-β/endoglin信号传导，导致肾小球内皮细胞窗孔丧失、细胞肿胀和蛋白尿。肾小球内皮被延伸到窗孔的糖萼和更松散结合的糖蛋白内皮细胞表面层覆盖。功能性选择透过性研究的数学分析得出结论，肾小球内皮细胞糖萼及其相关的表面层占循环中高达95%的蛋白质的保留。此外，窗孔对于维持肾小球毛细血管壁的高导水率是至关重要的，并且它们的损失导致肾小球滤过率的降低。结论：肾小球内皮细胞损伤可导致GFR下降和蛋白尿。版权所有（c）2007 S. Karger AG，巴塞尔。
Background: The endothelium that lines glomerular capillaries shares many properties with endothelial cells in general, but unlike most endothelial cells, it is extremely flat and densely perforated by transendothelial cell pores, the fenestrae. Until recently, it was believed that the fenestrae allow free passage of large proteins, and that the glomerular endothelium contributes little to the permselectivity of the glomerular capillary wall. Methods: Key studies addressing the nature of the glomerular capillary endothelium and its contribution to glomerular permselectivity were reviewed. Results: Glomerular endothelial cell flattening and fenestrae formation requires signals from differentiated podocytes, and from the glomerular basement membrane. Deletion of VEGF-A from podocytes prevents flattening and fenestration of glomerular endothelium. Application of VEGF- A to endothelial cells in vivo stimulates fenestrae formation, and neutralization of VEGF-A by soluble VEGF receptor 1 (sFlt-1) or anti-VEGF antibodies results in loss of glomerular fenestrae, and proteinuria. Neutralizing TGF-beta 1 antibodies, deletion of laminin alpha 3 in mice or laminin beta 3 in humans cause similar defects. The glomerular endotheliosis lesion of pre-eclampsia is due to the placenta-derived inhibitors sFlt-1 and sEndoglin, which block the VEGF-A/VEGF receptor and TGF-beta/endoglin signaling, respectively, causing the loss of glomerular endothelial cell fenestrae, cell swelling and proteinuria. The glomerular endothelium is covered by a glycocalyx that extends into the fenestrae and by a more loosely associated endothelial cell surface layer of glycoproteins. Mathematical analyses of functional permselectivity studies have concluded that the glomerular endothelial cell glycocalyx and its associated surface layer account for the retention of up to 95% of proteins within the circulation. Furthermore, the fenestrae are critical for the maintenance of the high hydraulic conductivity of the glomerular capillary wall, and their loss results in a reduction in the glomerular filtration rate. Conclusions: Loss of GFR and proteinuria can result from glomerular endothelial cell injury. Copyright (c) 2007 S. Karger AG, Basel.