TRPM2 mediates ischemic kidney injury and oxidant stress through RAC1
TRPM2 mediates ischemic kidney injury and oxidant stress through RAC1
复制标题
DOI：
10.1172/jci76042
复制
发表时间：
2014-11-01
影响因子：
15.9
通讯作者：
Reeves, W. Brian
中科院分区：
文献类型：
--
作者：
Gao, Guofeng;Wang, Weiwei;Reeves, W. Brian
缺血是急性肾损伤的主要原因。肾缺血与细胞离子稳态的丧失有关；然而，导致离子稳态功能障碍的途径尚不清楚。本研究在小鼠肾缺血/再灌注（I/R）损伤模型中评估了非选择性阳离子通道瞬时受体电位美拉他汀2 （TRPM2）。trpm2缺陷小鼠对缺血性损伤具有抵抗性，表现为肾功能改善、组织学损伤减轻、凋亡前通路抑制和炎症减轻。此外，药物抑制TRPM2对I/R损伤也有保护作用。TRPM2主要定位于肾近端小管上皮细胞，嵌合小鼠的研究表明，TRPM2的作用是由于在实质细胞而不是造血细胞中表达。缺血后，trpm2缺陷小鼠氧化应激减轻，NADPH氧化酶活性降低。虽然RAC1是NADPH氧化酶复合物的一个组成部分，但其与TRPM2和肾缺血损伤的关系尚不清楚。肾缺血后，TRPM2促进了RAC1的激活，活跃的RAC1与TRPM2物理相互作用，增加了TRPM2在细胞膜上的表达。最后，抑制RAC1可降低体内氧化应激和缺血性损伤。这些结果表明TRPM2依赖性的RAC1激活会增加氧化应激，并提示针对TRPM2和/或RAC1的治疗方法可能有效减轻缺血性肾损伤。
Ischemia is a leading cause of acute kidney injury. Kidney ischemia is associated with loss of cellular ion homeostasis; however, the pathways that underlie ion homeostasis dysfunction are poorly understood. Here, we evaluated the nonselective cation channel transient receptor potential melastatin 2 (TRPM2) in a murine model of kidney ischemia/reperfusion (I/R) injury. TRPM2-deficient mice were resistant to ischemic injury, as reflected by improved kidney function, reduced histologic damage, suppression of proapoptotic pathways, and reduced inflammation. Moreover, pharmacologic TRPM2 inhibition was also protective against I/R injury. TRPM2 was localized mainly in kidney proximal tubule epithelial cells, and studies in chimeric mice indicated that the effects of TRPM2 are due to expression in parenchymal cells rather than hematopoietic cells. TRPM2-deficient mice had less oxidative stress and lower levels of NADPH oxidase activity after ischemia. While RAC1 is a component of the NADPH oxidase complex, its relation to TRPM2 and kidney ischemic injury is unknown. Following kidney ischemia, TRPM2 promoted RAC1 activation, with active RAC1 physically interacting with TRPM2 and increasing TRPM2 expression at the cell membrane. Finally, inhibition of RAC1 reduced oxidant stress and ischemic injury in vivo. These results demonstrate that TRPM2-dependent RAC1 activation increases oxidant stress and suggest that therapeutic approaches targeting TRPM2 and/or RAC1 may be effective in reducing ischemic kidney injury.