Glyoxalase I overexpression ameliorates renal ischemia-reperfusion injury in rats
Glyoxalase I overexpression ameliorates renal ischemia-reperfusion injury in rats
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DOI：
10.1152/ajprenal.90575.2008
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发表时间：
2009-04-01
影响因子：
4.2
通讯作者：
Inagi, Reiko
中科院分区：
文献类型：
--
作者：
Kumagai, Takanori;Nangaku, Masaomi;Inagi, Reiko
Kumagai T，Nangaku M，Kojima I，永井R，Ingelfinger JR，Miyata T，Fujita T，Inagi R.过表达Gly Ⅰ减轻大鼠肾缺血再灌注损伤。美国肾脏生理学杂志296：F912-F921，2009年。首次发表于2009年2月11日; doi：10.1152/ajprenal.90575.2008。甲基乙二醛（MG）是一种由碳水化合物氧化和糖酵解产生的高活性羰基化合物，是蛋白质糖基化的主要前体，并诱导细胞毒性导致细胞凋亡。尽管最近的研究强调MG不仅在慢性氧化应激相关疾病中积累，而且在急性缺氧条件下也积累，但MG在急性疾病中的致病作用尚不清楚。MG通过谷胱甘肽酶系统（即谷胱甘肽酶I）有效代谢。我们研究了在大鼠肾缺血-再灌注（I/R）损伤中作为MG解毒剂的谷胱甘肽酶I的病理生理作用。I/R诱导的肾小管间质损伤与肾脏glycoprotein酶I活性的恶化相关，独立于其辅因子GSH，以及肾脏MG水平的增加。在体外研究中，与对照细胞相比，通过小干扰RNA转染在大鼠肾小管细胞中敲低glycosidase I，加剧了缺氧-复氧引起的细胞死亡。我们还研究了过表达人谷胱甘肽酶I的大鼠肾脏中的酶活性比野生型高17倍，过表达谷胱甘肽酶I是否能预防肾I/R损伤。这些大鼠I/R的组织学和功能表现显着改善，与细胞内MG加合物积聚、氧化应激和肾小管细胞凋亡的减少相关。总之，谷胱甘肽酶I通过减少MG在肾小管细胞中的积聚而在肾I/R损伤中发挥肾保护作用。
Kumagai T, Nangaku M, Kojima I, Nagai R, Ingelfinger JR, Miyata T, Fujita T, Inagi R. Glyoxalase I overexpression ameliorates renal ischemia-reperfusion injury in rats. Am J Physiol Renal Physiol 296: F912-F921, 2009. First published February 11, 2009; doi:10.1152/ajprenal.90575.2008.-Methylglyoxal (MG), a highly reactive carbonyl compound generated by carbohydrate oxidation and glycolysis, is the major precursor of protein glycation and induces cytotoxicity leading to apoptosis. Although recent studies have emphasized that MG accumulates in not only chronic oxidative stress-related diseases but also acute hypoxic conditions, the pathogenic contribution of MG in acute diseases is unclear. MG is efficiently metabolized by the glyoxalase system, namely, glyoxalase I. We investigated the pathophysiological role of glyoxalase I as an MG detoxifier in rat renal ischemia-reperfusion (I/R) injury. I/R-induced tubulointerstitial injury was associated with a deterioration in renal glyoxalase I activity independent of its cofactor, GSH, as well as an increase in renal MG level. In in vitro studies, knockdown of glyoxalase I by small interference RNA transfection in rat tubular cells exacerbated cell death by hypoxia-reoxygenation compared with control cells. We also examined whether glyoxalase I overexpression prevented renal I/R damage in rats overexpressing human glyoxalase I with enzyme activity in the kidney 17-fold higher than in wild-type. The histological and functional manifestations of I/R in these rats were significantly ameliorated in association with a decrease in intracellular MG adduct accumulation, oxidative stress, and tubular cell apoptosis. In conclusion, glyoxalase I exerts renoprotective effects in renal I/R injury via a reduction in MG accumulation in tubular cells.