CYTOPROTECTIVE EFFECTS OF GLYCINE AND GLUTATHIONE AGAINST HYPOXIC INJURY TO RENAL TUBULES
CYTOPROTECTIVE EFFECTS OF GLYCINE AND GLUTATHIONE AGAINST HYPOXIC INJURY TO RENAL TUBULES
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DOI：
10.1172/jci113224
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发表时间：
1987-11-01
影响因子：
15.9
通讯作者：
RAJAN, T
中科院分区：
文献类型：
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作者：
WEINBERG, JM;DAVIS, JA;RAJAN, T
先前在肾脏和其他组织中的工作表明，三肽、GSH和单个氨基酸在改变细胞对缺氧损伤的反应中所起的作用，但确切的相互关系还没有明确的定义。在体外低氧性损伤模型中，我们研究了GSH及其组成氨基酸和相关化合物对离体肾近端小管行为的影响。GSH是半胱氨酸、谷氨酸、甘氨酸和甘氨酸的组合，在缺氧30分钟时，当GSH单独存在时，对未处理的小管产生广泛的不可逆损伤，具有保护作用。当试剂浓度为0.25 mM时，保护效果显著，1 mM及以上时几乎完全保护。谷氨酸和半胱氨酸本身并不具有保护作用。加入到小管悬浮液中的外源GSH被迅速降解为其组成氨基酸。用GSH或半胱氨酸(而不是甘氨酸)处理肾小管，可增加细胞内GSH水平。氧化型GSH具有保护作用。丝氨酸、N-(2-硫代丙酰)-甘氨酸和一系列已知可以改善由活性氧代谢物造成的损伤的药物都没有益处。这些观察确定了甘氨酸在改变缺氧性肾小管细胞损伤过程中的一种新的和强有力的作用。这种影响与细胞GSH代谢的变化无关，似乎与细胞硫醇或活性氧代谢物的变化无关。进一步阐明其机制可能为深入了解缺氧诱导细胞损伤的基本病理生理机制和改善缺氧损伤提供一种实用的方法。
Roles for both the tripeptide, GSH, and individual amino acids in modifying the cellular response to oxygen deprivation-induced injury have been suggested by prior work in kidney and other tissues, but the precise interrelationships have not been clearly defined. We have studied the effects of GSH, its component amino acids, and related compounds on the behavior of isolated renal proximal tubules in a well characterized model of hypoxic injury in vitro. GSH, the combination of cysteine, glutamate, and glycine and glycine alone, when present in the medium during 30 min hypoxia, a duration sufficient to produce extensive irreversible injury in untreated tubules, were protective. Significant effects were detected at 0.25 mM concentrations of the reagents, and protection was nearly complete at concentrations of 1 mM and above. Glutamate and cysteine alone were not protective. The exogenous GSH added to the tubule suspensions was rapidly degraded to its component amino acids. Treatment of tubules with GSH or cysteine, but not glycine, increased intracellular GSH levels. Oxidized GSH was protective. Serine, N-(2-mercaptopropionyl)-glycine, and a panel of agents known to modify injury produced by reactive oxygen metabolites were without benefit. These observations identify a novel and potent action of glycine to modify the course of hypoxic renal tubular cell injury. This effect is independent of changes in cellular GSH metabolism and appears to be unrelated to alterations of cell thiols or reactive oxygen metabolites. Further elucidation of its mechanism may provide insight into both the basic pathophysiology of oxygen deprivation-induced cell injury and a practical way to ameliorate it.