Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, India.
J Surg Res. 2013 Aug;183(2):668-77. doi: 10.1016/j.jss.2013.01.040. Epub 2013 Feb 10.
Acute kidney injury (AKI) is one of the major health problems in developed as well as developing countries. The literature regarding the role of N-methyl-D-aspartate receptors (NMDAR) and the impact of the modulation of its allosteric sites on renal function is inadequate. The present study investigated the effect of modulating allosteric sites of NMDAR in ischemia-reperfusion-induced AKI.
We subjected rats to bilateral renal ischemia for 40 min followed by reperfusion for 24 h to induce AKI. We measured blood urea nitrogen, serum creatinine, uric acid, and lactate dehydrogenase to assess kidney injury. We assayed the thiobarbituric acid-reactive substances, reduced glutathione level, and myeloperoxidase and catalase activity to assess oxidative stress in renal tissue, and used hematoxylin-eosin staining to observe histopathologic changes.
Ischemia-reperfusion induced AKI, as demonstrated by an increase in serum parameters, oxidative stress and histopathologic changes in renal tissue. The NMDA agonist glutamic acid and polyamine binding site agonist spermidine significantly aggravated oxidative stress and ischemia-reperfusion-induced AKI. Various NMDA receptor antagonists, including glycine binding site inhibitor kynurenic acid, polyamine binding site inhibitor ketamine, and channel blocking agent magnesium sulfate, attenuated ischemia-reperfusion-induced AKI and significantly reduced oxidative stress, which suggests a role for NMDA receptors and the importance of regulating its allosteric sites in AKI.
Acute kidney injury is associated with the activation of NMDA receptors, as well as significant oxidative stress. The antagonism of various allosteric sites of NMDA receptors affords significant benefit against ischemia-reperfusion-induced AKI.
急性肾损伤（AKI）是发达国家和发展中国家的主要健康问题之一。关于 N-甲基-D-天冬氨酸受体（NMDAR）的作用及其变构位点调节对肾功能的影响的文献还不够充分。本研究探讨了调节 NMDAR 变构部位对缺血再灌注诱导的 AKI 的影响。
我们使大鼠双侧肾脏缺血 40 分钟，然后再灌注 24 小时，以诱导 AKI。我们测量了血尿素氮、血清肌酐、尿酸和乳酸脱氢酶，以评估肾脏损伤。我们测定了丙二醛反应物质、还原型谷胱甘肽水平、髓过氧化物酶和过氧化氢酶活性，以评估肾脏组织中的氧化应激，并使用苏木精-伊红染色观察组织病理学变化。
缺血再灌注引起 AKI，表现为血清参数增加、肾脏组织氧化应激和组织病理学变化。NMDA 激动剂谷氨酸和多胺结合位点激动剂精脒显著加重了氧化应激和缺血再灌注诱导的 AKI。各种 NMDA 受体拮抗剂，包括甘氨酸结合位点抑制剂氨基酮戊酸、多胺结合位点抑制剂氯胺酮和通道阻断剂硫酸镁，减轻了缺血再灌注诱导的 AKI，并显著降低了氧化应激，这表明 NMDA 受体在 AKI 中起作用，调节其变构部位的重要性。
急性肾损伤与 NMDA 受体的激活以及显著的氧化应激有关。拮抗各种 NMDA 受体的变构部位对缺血再灌注诱导的 AKI 有显著的益处。
