The Mitochondria-Targeted Antioxidant Mitoquinone Protects against Cold Storage Injury of Renal Tubular Cells and Rat Kidneys
The Mitochondria-Targeted Antioxidant Mitoquinone Protects against Cold Storage Injury of Renal Tubular Cells and Rat Kidneys
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DOI：
10.1124/jpet.110.176743
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发表时间：
2011-03-01
影响因子：
3.5
通讯作者：
MacMillan-Crow, Lee Ann
中科院分区：
文献类型：
--
作者：
Mitchell, Tanecia;Rotaru, Dumitru;MacMillan-Crow, Lee Ann
大多数用于移植的肾脏来自已故捐赠者。这些肾脏在移植前必须进行低温保存/储存，以保持组织质量，并为受体的选择和运输留出时间。然而，冷冻储存（CS）可能导致移植后组织损伤、肾脏丢弃或长期肾功能不全。我们之前已经确定线粒体超氧化物和其他下游氧化剂是导致大鼠肾近端小管细胞CS + rewarming （RW）损伤的重要信号分子。因此，本研究的目的是确定在威斯康星大学（UW）保存液中添加线粒体靶向抗氧化剂mitoquinone （MitoQ）是否能对CS损伤提供保护。将肾细胞或离体大鼠肾脏单独置于UW溶液中（4℃下4小时）或含有MitoQ或其对照化合物decyltriphenylphosphonium bromide （DecylTPP）的UW溶液中（体外1 μ M，离体100 μ M）。在CS暴露后，评估了氧化剂的产生、线粒体功能、细胞活力和肾脏形态的改变。CS诱导线粒体超氧化物生成和酪氨酸硝化增加2- 3倍，线粒体复合物部分失活，细胞死亡和/或肾损伤显著增加。MitoQ处理减少了2倍的氧化剂产生，完全防止了线粒体功能障碍，并显著改善了细胞活力和/或肾脏形态，而DecylTPP处理没有提供任何保护。这些发现表明，MitoQ可能有潜在的治疗用途，可以减少器官保存损伤和肾脏丢弃，并/或可能改善移植后的肾功能。
The majority of kidneys used for transplantation are obtained from deceased donors. These kidneys must undergo cold preservation/storage before transplantation to preserve tissue quality and allow time for recipient selection and transport. However, cold storage (CS) can result in tissue injury, kidney discardment, or long-term renal dysfunction after transplantation. We have previously determined mitochondrial superoxide and other downstream oxidants to be important signaling molecules that contribute to CS plus rewarming (RW) injury of rat renal proximal tubular cells. Thus, this study's purpose was to determine whether adding mitoquinone (MitoQ), a mitochondria-targeted antioxidant, to University of Wisconsin (UW) preservation solution could offer protection against CS injury. CS was initiated by placing renal cells or isolated rat kidneys in UW solution alone (4 h at 4 degrees C) or UW solution containing MitoQ or its control compound, decyltriphenylphosphonium bromide (DecylTPP) (1 mu M in vitro; 100 mu M ex vivo). Oxidant production, mitochondrial function, cell viability, and alterations in renal morphology were assessed after CS exposure. CS induced a 2- to 3-fold increase in mitochondrial superoxide generation and tyrosine nitration, partial inactivation of mitochondrial complexes, and a significant increase in cell death and/or renal damage. MitoQ treatment decreased oxidant production similar to 2-fold, completely prevented mitochondrial dysfunction, and significantly improved cell viability and/or renal morphology, whereas DecylTPP treatment did not offer any protection. These findings implicate that MitoQ could potentially be of therapeutic use for reducing organ preservation damage and kidney discardment and/or possibly improving renal function after transplantation.