A uremic toxin, 3-carboxy-4-methyl-5-propyl-2-furanpropionate induces cell damage to proximal tubular cells via the generation of a radical intermediate
A uremic toxin, 3-carboxy-4-methyl-5-propyl-2-furanpropionate induces cell damage to proximal tubular cells via the generation of a radical intermediate
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DOI：
10.1016/j.bcp.2012.07.033
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发表时间：
2012-11-01
影响因子：
5.8
通讯作者：
Maruyama, Toru
中科院分区：
文献类型：
--
作者：
Miyamoto, Yohei;Iwao, Yasunori;Maruyama, Toru
3-羧基-4-甲基-5-丙基-2-呋喃丙酸(CMPF)是一种呋喃脂肪酸尿毒症毒素(UT)，是有机离子转运体的底物，可促进CMPF在肾小管上皮细胞中的积聚。尽管UTS诱导的氧化应激被认为是其在慢性肾脏疾病中的毒性机制之一，但关于CMPF的氧化还原特性及其与肾细胞损伤的关系的信息很少。这些结果表明，在血管紧张素II(A-II)的存在下，CMPF可促进HK-2细胞产生活性氧(ROS)，血管紧张素II是O-2(中心点-)的诱导剂。当铁也存在时，CMPF和A-II诱导Fenton反应，导致ROS产生进一步增加。CMPF诱导的氧化应激增加了HK-2细胞分泌的转化生长因子-β1，并且CMPF诱导的ROS的产生与活性的转化生长因子-β1的分泌呈正相关。CMPF导致细胞存活率下降，与细胞内ROS生成呈负相关。有机阴离子转运抑制剂丙磺舒可完全抑制CMPF对HK-2细胞的上述负性作用。有趣的是，体外ROS分析表明，CMPF直接与超氧阴离子自由基(O-2(中心点))和过氧化自由基(LOO中心点)相互作用产生CMPF自由基。随后CMPF自由基与溶解氧的相互作用导致O-2(中心点-)的过量产生。基于这些发现，我们得出结论，CMPF积聚在肾脏细胞中，似乎发挥了显著的促氧化剂作用，从而通过过量产生O-2(中心点-)而导致肾细胞损伤。皇冠版权所有(C)2012由爱思唯尔公司出版。保留所有权利。
3-Carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), a furan fatty acid uremic toxin (UT) and a substrate for organic ion transporters, contributes to the accumulation of CMPF in renal tubular cells. Although oxidative stress induced by UTs has been proposed as a mechanism of its toxicity in chronic kidney disease, little information is available regarding the redox property of CMPF and its relation to renal cell damage. The findings herein show that CMPF enhances the production of reactive oxygen species (ROS) in HK-2 cells in the presence of angiotensin II (A-II), an inducer of O-2(center dot-). When iron is also present, CMPF and A-II induce the Fenton reaction, resulting in a further increase in ROS production. Such CMPF-induced oxidative stress increases TGF-beta 1secretion in HK-2 cells, and a positive correlation between CMPF-induced ROS production and the secretion of active TGF-beta 1 was observed. CMPF caused a reduction in cell viability which was negatively correlated with intracellular ROS production. These negative effects of CMPF in HK-2 cells were completely suppressed by probenecid, an inhibitor of organic anion transport. Interestingly, in vitro ROS assays indicate that CMPF directly interacts with superoxide anion radicals (O-2(center dot-)) and peroxy radicals (LOO center dot) to produce CMPF radicals. The subsequent interaction of CMPF radicals with dissolved oxygen leads to the overproduction of O-2(center dot-). Based on these findings, we conclude that CMPF, which accumulates in the renal cells, appears to play a prominent role as a pro-oxidant which subsequently leads to renal cellular damage via the overproduction of O-2(center dot-). Crown Copyright (C) 2012 Published by Elsevier Inc. All rights reserved.