Perico N, Delaini F, Tagliaferri M, Abbate M, Cucchi M, Bertani T, Remuzzi G
Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Lab Invest. 1988 Feb;58(2):163-71.
Platelet-activating factor (PAF) is a lipid mediator of inflammation believed to play a role in glomerulonephritis by favoring immune complex formation and modulating the subsequent inflammatory reaction. Some evidence indicates that PAF may also be one of the mediators of proteinuria. Previous work suggested that PAF can increase glomerular permeability to proteins, activating platelets and inflammatory cells to release cationic proteins. In the present study, we addressed the possibility that PAF might directly increase glomerular permeability to proteins independently of platelets and inflammatory cells. We used a preparation of isolated rat kidney perfused with an artificial cell-free medium. After stabilization and two 10-minute control clearance periods, kidneys perfused in a closed circuit were exposed to PAF (2 nM or 10 nM final concentration) or 2-lyso-PAF (10 nM final concentration) or vehicle for 40 minutes. Glomerular filtration rate, measured as creatinine clearance, and renal vascular resistance did not significantly change when either PAF (2 nM or 10 nM) or 2-lyso-PAF, or vehicle were added to the perfusion fluid. Unlike vehicle or 2-lyso-PAF, addition of PAF at the final concentration of 2 and 10 nM to the perfusate produced a dose-dependent progressive increase in urinary protein excretion. PAF-induced proteinuria was prevented by L-652,731, a specific PAF receptor antagonist, suggesting that PAF's effect on glomerular permeability to proteins is likely to be related to its biologic activity. Several pharmacologic manipulations addressed to the potential mediators of PAF effect on glomerular permeability to proteins would exclude that the effect of PAF on isolated perfused kidney is mediated by cyclooxygenase or lipoxygenase products, or is the result of oxygen-free radical generation. The possibility that PAF enhances glomerular permeability to proteins by changing the glomerular barrier electrostatic properties was explored using polyethylene-imine. Electron microscopy examination revealed no difference in the distribution of electron-dense deposits along the glomerular basement membrane in kidneys exposed to 10 nM PAF or vehicle.
血小板活化因子（PAF）是一种炎症脂质介质，被认为通过促进免疫复合物形成和调节随后的炎症反应在肾小球肾炎中发挥作用。一些证据表明，PAF也可能是蛋白尿的介质之一。先前的研究表明，PAF可增加肾小球对蛋白质的通透性，激活血小板和炎症细胞以释放阳离子蛋白。在本研究中，我们探讨了PAF可能独立于血小板和炎症细胞直接增加肾小球对蛋白质通透性的可能性。我们使用一种用无细胞人工培养基灌注的离体大鼠肾脏制剂。在稳定期和两个10分钟的对照清除期后，在闭路中灌注的肾脏暴露于PAF（终浓度2 nM或10 nM）或2-溶血-PAF（终浓度10 nM）或溶剂中40分钟。当将PAF（2 nM或10 nM）或2-溶血-PAF或溶剂添加到灌注液中时，以肌酐清除率测量的肾小球滤过率和肾血管阻力没有显著变化。与溶剂或2-溶血-PAF不同，在灌注液中添加终浓度为2 nM和10 nM的PAF会导致尿蛋白排泄呈剂量依赖性逐渐增加。特异性PAF受体拮抗剂L-652,731可预防PAF诱导的蛋白尿，这表明PAF对肾小球对蛋白质通透性的影响可能与其生物学活性有关。针对PAF对肾小球对蛋白质通透性影响的潜在介质进行的几种药理操作排除了PAF对离体灌注肾脏的作用是由环氧化酶或脂氧化酶产物介导的，也不是由氧自由基生成导致的可能性。使用聚乙烯亚胺探讨了PAF通过改变肾小球屏障静电特性增强肾小球对蛋白质通透性的可能性。电子显微镜检查显示，暴露于10 nM PAF或溶剂的肾脏中，沿肾小球基底膜的电子致密沉积物分布没有差异。
