Superoxide dismutase mimetic preserves the glomerular capillary permeability barrier to protein
Superoxide dismutase mimetic preserves the glomerular capillary permeability barrier to protein
复制标题
DOI：
10.1124/jpet.105.092957
复制
发表时间：
2006-03-01
影响因子：
3.5
通讯作者：
Lianos, EA
中科院分区：
文献类型：
--
作者：
Duann, P;Datta, PK;Lianos, EA
超氧化物（O-2（.-））的过量产生发生在肾小球疾病，并可能超过超氧化物歧化酶（SOD）的能力，从而加强O-2（.-）的氧化损伤以及破坏肾小球毛细血管对蛋白质的渗透性屏障的相关自由基种类。我们使用1）抗肾小球基底膜抗体（抗GBM）诱导的肾小球免疫损伤大鼠模型，和2）由细胞因子诱导的损伤的分离大鼠肾小球，检查了SOD模拟物tempol在保护肾小球蛋白质渗透性方面的功效肿瘤坏死因子-α（TNF-α）。为了诱导肾小球免疫损伤，大鼠使用导致巨噬细胞显著浸润肾小球的方案接受抗GBM，其中巨噬细胞来源的TNF α已显示介导白蛋白尿。为了增加肾小球毛细血管对白蛋白（P-alb）的通透性，将分离的肾小球与已知刺激O-2（.-）的浓度（0.5 - 4.0 μ g/ml）的TNF α孵育。生产P-alb的增加通过测量肾小球体积的变化来检测。在肾小球免疫损伤大鼠中观察到白蛋白和F-2 α-异前列腺素的尿排泄显著增加，而收缩压无显著变化。Tempol治疗显著减少尿异前列腺素和白蛋白排泄。在离体肾小球中，TNF α增加P-alb和tempol消除这种影响，两者都以剂量依赖性方式。这些观察结果表明，SOD模拟物可以保护肾小球通透性屏障蛋白质的氧化应激条件下，从O-2（.-）生产
Overproduction of superoxide (O-2(.-)) occurs in glomerular disease and may overwhelm the capacity of superoxide dismutase ( SOD), thereby intensifying oxidant injury by O-2(.-) and related radical species that disrupt the glomerular capillary permeability barrier to protein. We examined the efficacy of the SOD mimetic tempol in preserving glomerular permeability to protein using 1) a rat model of glomerular immune injury induced by an antiglomerular basement membrane antibody (anti-GBM), and 2) isolated rat glomeruli in which injury was induced by the cytokine tumor necrosis factor-alpha (TNF alpha). To induce glomerular immune injury, rats received anti-GBM using a protocol that results in prominent infiltration of glomeruli by macrophages and in which macrophage-derived TNF alpha has been shown to mediate albuminuria. To increase glomerular capillary permeability to albumin (P-alb) ex vivo, isolated glomeruli were incubated with TNF alpha at concentrations (0.5 - 4.0 mu g/ml) known to stimulate O-2(.-) production. Increments in P-alb were detected by measuring changes in glomerular volume in response to an applied oncotic gradient. Significant increases in the urine excretion of albumin and F-2 alpha-isoprostane were observed in rats with glomerular immune injury without a significant change in systolic blood pressure. Tempol treatment significantly reduced urine isoprostane and albumin excretion. In isolated glomeruli, TNF alpha increased P-alb and tempol abrogated this effect, both in a dose-dependent manner. These observations indicate that SOD mimetics can preserve the glomerular permeability barrier to protein under conditions of oxidative stress from O-2(.-) production.