The Role of Selections in The Formation of Glomerular Thrombi

本研究的目的是探讨选择素和选择素配体在肾小球血栓形成中的作用，因为肾小球血栓可发生多种肾小球疾病，并且是进行性肾损伤的重要病理参数。本研究旨在探讨P-选择素在肾小球血栓形成中的作用及人工合成的选择素阻滞剂的治疗作用。在实验的第一部分，采用肾下注射内毒素和肾毒性球蛋白所致的血栓性微血管病大鼠模型，获得以下结果。(1)微血栓的形成完全依赖于肾小球内白细胞的浸润，因为环磷酰胺耗尽了循环中的白细胞，完全阻断了血栓的形成。(2)P-选择素在肾小球有选择性表达。抗P-选择素抗体在10分钟时显著阻断了血小板在肾小球的聚集，并显著抑制了…6h更能阻断白细胞的渗入和血栓的形成。(3)P-选择素受体阻断型合成硫脂衍生物(SKK-60037)对肾小球血栓形成的保护作用与抗P-选择素抗体相似。这些结果表明P-选择素在微血栓形成过程中起重要作用，合成硫脂衍生物(SKK-60037)可能在进行性肾损伤的临床应用中发挥作用。第二部分研究了N-乙酰氨基葡萄糖-6-O-磺基转移酶在胎肾中的表达。结果表明，虽然N-乙酰氨基葡萄糖-6-O-磺基转移酶在胎肾上皮细胞中有显著表达，但在胎肾中未检测到6-磺基Lewis X或6-磺基唾液酸基Lewis X等表位。这些结果表明，岩藻糖基转移酶和/或唾液酸基转移酶的额外表达可能是肾脏中选择素配体表达所必需的。较少

The aim of this project was to investigate the role of selections and selectin ligands in the formation of glomerular thrombi, since glomerular thrombi occurs various glomerular diseases and is an important pathological parameter for the progressive renal injuries. In the present study, the role of P-selectin in the formation of glomerular thrombi and the therapeutical effects of synthetic selectin blocker were studied. In the first part of experiment using a rat model of thrombotic microangiopathy induced by injection of subnephritic dose of LPS followed by nephrotoxic globulin,the following results were obtained. (1) The formation of microthrombi completely depended on the leukocyte infiltration in glomeruli, since depletion of circulating leukocytes by cyclophosphamide completely blocked the formation on thrombi. (2) Selective expression of P-selectin in glomeruli was detected. Anti P-selectin antibody prominently blocked platelets aggregation in glomeruli at 10 minutes, and signifi … More cantly blocked the infiltration of leukocytes and the formation thrombi at 6 hrs. (3) P-selectin receptor-blocking synthetic sulfatide derivative (SKK-60037) showed similar protective effects on the formation glomerular thrombi as those of anti P-selection antibody. These results indicate that P-selectin was significantly involved in the process of the formation on microthrombi, and synthetic sulfatide derivative (SKK-60037) may have potential for clinical application of progressive renal injuries. In the second part, the expression of N-acetylglucosamine-6-o-sulfotransferase mRNA was detected in the epitopes induced by this enzyme in fetal kidneys was studied. The results were as follow ; although prominent expression of N-acetylglucosamine-6-o-sulfotransferase mRNA was detected in the epithelial cells, the epitopes such as 6-sulfo LewisX or 6-sulfo sialyl Lewis X were not detected in fetal kidneys. These results indicate that the additional expression of fucosyltransferases and/or sialyltransferases might be requisite for expression of selectin ligands in the kidney. Less