Microvascular Research Laboratories, School of Physiology and Pharmacology, University of Bristol, Southwell Street, Bristol, UK.
J Am Soc Nephrol. 2012 Aug;23(8):1339-50. doi: 10.1681/ASN.2012010017. Epub 2012 Jul 12.
Patients with albuminuria and CKD frequently have vascular dysfunction but the underlying mechanisms remain unclear. Because the endothelial surface layer, a meshwork of surface-bound and loosely adherent glycosaminoglycans and proteoglycans, modulates vascular function, its loss could contribute to both renal and systemic vascular dysfunction in proteinuric CKD. Using Munich-Wistar-Fromter (MWF) rats as a model of spontaneous albuminuric CKD, multiphoton fluorescence imaging and single-vessel physiology measurements revealed that old MWF rats exhibited widespread loss of the endothelial surface layer in parallel with defects in microvascular permeability to both water and albumin, in both continuous mesenteric microvessels and fenestrated glomerular microvessels. In contrast to young MWF rats, enzymatic disruption of the endothelial surface layer in old MWF rats resulted in neither additional loss of the layer nor additional changes in permeability. Intravenous injection of wheat germ agglutinin lectin and its adsorption onto the endothelial surface layer significantly improved glomerular albumin permeability. Taken together, these results suggest that widespread loss of the endothelial surface layer links albuminuric kidney disease with systemic vascular dysfunction, providing a potential therapeutic target for proteinuric kidney disease.
患有白蛋白尿和 CKD 的患者常伴有血管功能障碍，但潜在机制尚不清楚。由于内皮表面层是一层由表面结合和松散附着的糖胺聚糖和蛋白聚糖组成的网状结构，调节血管功能，其丢失可能导致蛋白尿性 CKD 中的肾血管和全身血管功能障碍。使用慕尼黑威斯特伐利亚-弗罗默特（MWF）大鼠作为自发性白蛋白尿 CKD 的模型，多光子荧光成像和单血管生理学测量显示，老年 MWF 大鼠表现出广泛的内皮表面层丢失，同时对水和白蛋白的微血管通透性均存在缺陷，在连续肠系膜微血管和有孔肾小球微血管中均存在这种现象。与年轻的 MWF 大鼠不同，在老年 MWF 大鼠中酶促破坏内皮表面层既不会导致层进一步丢失，也不会导致通透性发生进一步变化。静脉注射麦胚凝集素（wheat germ agglutinin lectin）及其吸附在内皮表面层上，可显著改善肾小球白蛋白通透性。综上所述，这些结果表明，内皮表面层的广泛丢失将白蛋白尿性肾病与全身血管功能障碍联系起来，为蛋白尿性肾病提供了一个潜在的治疗靶点。
