Zager R A
Department of Medicine, University of Washington, Seattle.
Circ Res. 1993 Nov;73(5):926-34. doi: 10.1161/01.res.73.5.926.
Intracellular iron reportedly mediates many forms of tissue injury, including ischemic and myohemoglobinuric acute renal failure. This action may be explained by the ability of iron to catalyze the formation of the highly toxic hydroxyl radical (.OH) from H2O2 via the Fenton/Haber-Weiss reactions. To assess whether renal tubular myoglobin/iron loading, induced by a physiological mechanism (endocytosis), alters its susceptibility to O2 deprivation/reoxygenation- and H2O2-mediated injury, rats were infused with myoglobin or its vehicle (5% dextrose, control rats), and after 2 hours, proximal tubular segments (PTSs) were isolated for study. This infusion caused substantial myoglobin endocytic uptake (approximately 25 micrograms/mg PTS protein), and it doubled PTS catalytic iron content (assessed by bleomycin assay). Nevertheless, PTS viability (percent lactate dehydrogenase release) was minimally affected (4% to 6% increase), and an increased .OH burden (assessed by the salicylate trap method) did not appear to result. Deferoxamine addition, reported to protect against in vivo acute renal failure, paradoxically increased .OH levels (approximately 25%) in myoglobin-loaded, but not control, PTSs. Conversely, dimethylthiourea (an .OH scavenger) depressed .OH (by approximately 80%) in all PTSs. Myoglobin/iron loading modestly increased PTS vulnerability to exogenous H2O2 addition (P < .001). However, tubular susceptibility to hypoxia (15 and 30 minutes)/reoxygenation injury was not affected. .OH levels appeared to fall in response to both forms of injury, suggesting decreased .OH production and/or .OH scavenging. To assess whether myoglobin decreases .OH levels in the presence of Fenton reactants, myoglobin and six other test proteins were incubated with Fe2+/H2O2. Myoglobin decreased .OH levels by approximately 70%, a significantly greater decrement than was observed with the other proteins tested.(ABSTRACT TRUNCATED AT 250 WORDS)
据报道，细胞内铁介导多种形式的组织损伤，包括缺血性和肌红蛋白尿性急性肾衰竭。这种作用可以通过铁能够通过芬顿/哈伯-维伊斯反应催化由过氧化氢形成剧毒的羟基自由基（·OH）来解释。为了评估由生理机制（内吞作用）诱导的肾小管肌红蛋白/铁负荷是否会改变其对缺氧/复氧和过氧化氢介导的损伤的易感性，给大鼠输注肌红蛋白或其载体（5%葡萄糖，对照大鼠），2小时后，分离近端肾小管节段（PTS）进行研究。这种输注导致大量肌红蛋白通过内吞作用摄取（约25微克/毫克PTS蛋白），并且使PTS催化铁含量增加了一倍（通过博来霉素测定法评估）。然而，PTS活力（乳酸脱氢酶释放百分比）受到的影响最小（增加4%至6%），并且似乎没有导致·OH负荷增加（通过水杨酸盐捕获法评估）。据报道可预防体内急性肾衰竭的去铁胺，反而使负载肌红蛋白的PTS中的·OH水平增加（约25%），而对照PTS则未增加。相反，二甲基硫脲（一种·OH清除剂）使所有PTS中的·OH降低（约80%）。肌红蛋白/铁负荷适度增加了PTS对外源添加过氧化氢的易感性（P<.001）。然而，肾小管对缺氧（15和30分钟）/复氧损伤的易感性不受影响。两种形式的损伤均使·OH水平下降，提示·OH生成减少和/或·OH清除增加。为了评估在存在芬顿反应物的情况下肌红蛋白是否会降低·OH水平，将肌红蛋白和其他六种测试蛋白与Fe2+/H2O2一起孵育。肌红蛋白使·OH水平降低了约70%，比其他测试蛋白观察到的降低幅度明显更大。（摘要截短于250字）
