Zager R A, Fuerstenberg S M, Baehr P H, Myerson D, Torok-Storb B
Fred Hutchinson Cancer Research Center, Seattle, WA 98104.
J Am Soc Nephrol. 1994 Feb;4(8):1588-97. doi: 10.1681/ASN.V481588.
Xanthine oxidase (XO) activity and hydroxyl radical (.OH) formation are widely proposed mediators of renal reperfusion injury, potentially altering the severity of, and recovery from, postischemic acute renal failure. The goal of this study was to ascertain whether combination XO inhibitor (oxypurinol) and .OH scavenger (Na benzoate) therapy, given at the time of renal ischemia, alters the extent of: (1) tubular necrosis and filtration failure; (2) DNA fragmentation/apoptosis (assessed in situ by terminal deoxynucleotidyl transferase reactivity); (3) early tubular regenerative responses (proliferating cell nuclear antigen expression; (3H)thymidine incorporation); and (4) the rate and/or degree of functional and morphologic repair. The effects of XO inhibition, .OH scavengers, and "catalytic" iron (FeSO4) on human proximal tubular cell proliferation in vitro were also assessed with a newly established cell line (HK-2). Male Sprague-Dawley rats were subjected to 35 min of bilateral renal arterial occlusion with or without oxypurinol/benzoate therapy. These agents did not alter the extent of tubular necrosis or filtration failure, proliferating cell nuclear antigen expression or thymidine incorporation, or the rate/extent of renal functional/morphologic repair. DNA fragmentation did not precede tubular necrosis, and it was unaffected by antioxidant therapy. By 5 days postischemia, both treatment groups demonstrated regenerating epithelial fronds that protruded into the lumina. These structures contained terminal deoxynucleotidyl transferase-reactive, but morphologically intact, cells, suggesting the presence of apoptosis. Oxypurinol and .OH scavengers (benzoate; dimethylthiourea) suppressed in vitro tubular cell proliferation; conversely, catalytic Fe had a growth-stimulatory effect. These results suggest that: (1) XO inhibition/.OH scavenger therapy has no discernible net effect on postischemic acute renal failure; (2) DNA fragmentation does not precede tubular necrosis, suggesting that it is not a primary mediator of ischemic cell death; and (3) antioxidants can be antiproliferative for human tubular cells, possibly mitigating their potential beneficial effects.
黄嘌呤氧化酶（XO）活性和羟自由基（·OH）的形成被广泛认为是肾再灌注损伤的介质，可能会改变缺血后急性肾衰竭的严重程度及恢复情况。本研究的目的是确定在肾缺血时给予XO抑制剂（氧嘌呤醇）和·OH清除剂（苯甲酸钠）联合治疗是否会改变以下方面的程度：（1）肾小管坏死和滤过功能衰竭；（2）DNA片段化/凋亡（通过末端脱氧核苷酸转移酶反应原位评估）；（3）早期肾小管再生反应（增殖细胞核抗原表达；[3H]胸腺嘧啶核苷掺入）；以及（4）功能和形态修复的速率和/或程度。还使用新建立的细胞系（HK-2）评估了XO抑制、·OH清除剂和“催化性”铁（硫酸亚铁）对体外人近端肾小管细胞增殖的影响。雄性Sprague-Dawley大鼠接受35分钟的双侧肾动脉闭塞，伴或不伴有氧嘌呤醇/苯甲酸钠治疗。这些药物并未改变肾小管坏死或滤过功能衰竭的程度、增殖细胞核抗原表达或胸腺嘧啶核苷掺入，也未改变肾功能/形态修复的速率/程度。DNA片段化在肾小管坏死之前并未出现，且不受抗氧化治疗的影响。缺血后5天时，两个治疗组均显示有再生的上皮小叶突入管腔。这些结构含有末端脱氧核苷酸转移酶反应阳性但形态完整的细胞，提示存在凋亡。氧嘌呤醇和·OH清除剂（苯甲酸钠；二甲基硫脲）抑制体外肾小管细胞增殖；相反，催化性铁具有生长刺激作用。这些结果表明：（1）XO抑制/·OH清除剂治疗对缺血后急性肾衰竭没有明显的净效应；（2）DNA片段化在肾小管坏死之前并未出现，提示其不是缺血性细胞死亡的主要介质；（3）抗氧化剂可能对人肾小管细胞具有抗增殖作用，从而可能减轻其潜在的有益作用。
