Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
Antioxid Redox Signal. 2010 Oct 1;13(7):975-86. doi: 10.1089/ars.2010.3091.
This study investigated the role of NMDA receptor in hyperhomocyteinemia (hHcys)-induced NADPH oxidase (Nox) activation and glomerulosclerosis. Sprague-Dawley rats were fed a folate-free (FF) diet to produce hHcys, and a NMDA receptor antagonist, MK-801, was administrated. Rats fed the FF diet exhibited significantly increased plasma homocysteine levels, upregulated NMDA receptor expression, enhanced Nox activity and Nox-dependent O(2)(.-) production in the glomeruli, which were accompanied by remarkable glomerulosclerosis. MK-801 treatment significantly inhibited Nox-dependent O(2)(.-) production induced by hHcys and reduced glomerular damage index as compared with vehicle-treated hHcys rats. Correspondingly, glomerular deposition of extracellular matrix components in hHcys rats was ameliorated by the administration of MK-801. Additionally, hHcys induced an increase in tissue inhibitor of metalloproteinase-1 (TIMP-1) expression and a decrease in matrix metalloproteinase (MMP)-1 and MMP-9 activities, all of which were abolished by MK-801 treatment. In vitro studies showed that homocysteine increased Nox-dependent O(2)(.-) generation in rat mesangial cells, which was blocked by MK-801. Pretreatment with MK-801 also reversed homocysteine-induced decrease in MMP-1 activity and increase in TIMP-1 expression. These results support the view that the NMDA receptor may mediate Nox activation in the kidney during hHcys and thereby play a critical role in the development of hHcys-induced glomerulosclerosis.
本研究探讨了 NMDA 受体在高同型半胱氨酸血症（hHcys）诱导的 NADPH 氧化酶（Nox）激活和肾小球硬化中的作用。使用叶酸缺乏（FF）饮食喂养 Sprague-Dawley 大鼠以产生 hHcys，并给予 NMDA 受体拮抗剂 MK-801。FF 饮食喂养的大鼠表现出明显升高的血浆同型半胱氨酸水平，上调的 NMDA 受体表达，增强了肾小球中的 Nox 活性和 Nox 依赖性 O2(-)产生，这伴随着明显的肾小球硬化。与 vehicle 处理的 hHcys 大鼠相比，MK-801 治疗显著抑制了 hHcys 诱导的 Nox 依赖性 O2(-)产生，并降低了肾小球损伤指数。相应地，MK-801 的给药改善了 hHcys 大鼠肾小球细胞外基质成分的沉积。此外，hHcys 诱导组织金属蛋白酶抑制剂-1（TIMP-1）表达增加，基质金属蛋白酶（MMP）-1 和 MMP-9 活性降低，所有这些均被 MK-801 治疗所消除。体外研究表明，同型半胱氨酸增加了大鼠系膜细胞中 Nox 依赖性 O2(-)的产生，这被 MK-801 阻断。MK-801 的预处理还逆转了同型半胱氨酸诱导的 MMP-1 活性降低和 TIMP-1 表达增加。这些结果支持 NMDA 受体可能在 hHcys 期间介导肾脏中的 Nox 激活，从而在 hHcys 诱导的肾小球硬化的发展中发挥关键作用的观点。
