White R B, Lowrie L, Stork J E, Iskandar S S, Lamm M E, Emancipator S N
Institute of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio.
J Clin Invest. 1991 May;87(5):1819-27. doi: 10.1172/JCI115203.
We sought to determine whether systemic administration of proteases ameliorates membranous nephritis induced in rats by immunization and challenge with cationic bovine gamma globulin, and whether targeting of protease to glomerular capillaries increases efficacy. Proteases substituted with biotin were targeted via the cationic protein avidin A, which by virtue of its charge has affinity for the glomerular basement membrane. Despite identical pretreatment proteinuria, rats given untargeted protease (biotin-conjugated without avidin, or unconjugated plus avidin) had significantly less proteinuria than saline-treated controls and nephrotic rats given avidin plus biotin-conjugated (targeted) protease had even less proteinuria and reduced glomerular rat IgG and C3. Among more severely nephrotic rats, targeted protease was again more effective than untargeted protease at reducing proteinuria, and also decreased the size of electron-dense glomerular deposits, hypercholesterolemia, and creatininemia. Inactivated targeted proteases had no effect on proteinuria, hypercholesterolemia, or azotemia. Finally, active targeted protease did not affect proteinuria in the nonimmune mediated nephrosis induced by puromycin aminonucleoside. We conclude that systemic protease can specifically diminish glomerular immune deposits, proteinuria, hyperlipidemia, and creatininemia associated with experimental immune complex glomerulonephritis but not toxic nephrosis, and that targeted protease is more effective than untargeted protease.
我们试图确定全身性给予蛋白酶是否能改善通过用阳离子牛γ球蛋白免疫和攻击诱导的大鼠膜性肾病，以及将蛋白酶靶向肾小球毛细血管是否能提高疗效。用生物素替代的蛋白酶通过阳离子蛋白抗生物素蛋白A靶向，抗生物素蛋白A因其电荷对肾小球基底膜具有亲和力。尽管预处理蛋白尿相同，但给予非靶向蛋白酶的大鼠（生物素偶联但无抗生物素蛋白，或未偶联加抗生物素蛋白）的蛋白尿明显少于生理盐水处理的对照组，而给予抗生物素蛋白加生物素偶联（靶向）蛋白酶的肾病大鼠蛋白尿甚至更少，肾小球大鼠IgG和C3减少。在更严重的肾病大鼠中，靶向蛋白酶在减少蛋白尿方面再次比非靶向蛋白酶更有效，并且还减小了电子致密性肾小球沉积物的大小、高胆固醇血症和肌酐血症。灭活的靶向蛋白酶对蛋白尿、高胆固醇血症或氮质血症没有影响。最后，活性靶向蛋白酶对嘌呤霉素氨基核苷诱导的非免疫介导性肾病中的蛋白尿没有影响。我们得出结论，全身性蛋白酶可以特异性减少与实验性免疫复合物肾小球肾炎相关的肾小球免疫沉积物、蛋白尿、高脂血症和肌酐血症，但对中毒性肾病无效，并且靶向蛋白酶比非靶向蛋白酶更有效。
