Department of Medicine, Division of Nephrology, Baylor College of Medicine, The University of Western Ontario, London, Ontario, Canada.
Kidney Int. 2012 Oct;82(8):867-77. doi: 10.1038/ki.2012.223. Epub 2012 Jun 13.
Reactive oxygen species, endothelial dysfunction, inflammation, and mitogen-activated protein kinases have important roles in the pathogenesis of ischemia/reperfusion kidney injury. Stanniocalcin-1 (STC1) suppresses superoxide generation in many systems through the induction of mitochondrial uncoupling proteins and blocks the cytokine-induced rise in endothelial permeability. Here we tested whether transgenic overexpression of STC1 protects from bilateral ischemia/reperfusion kidney injury. This injury in wild-type mice caused a halving of the creatinine clearance; severe tubular vacuolization and cast formation; increased infiltration of macrophages and T cells; higher vascular permeability; greater production of superoxide and hydrogen peroxide; and higher ratio of activated extracellular regulated kinase/activated Jun-N-terminal kinase and p38, all compared to sham-treated controls. Mice transgenic for human STC1 expression, however, had resistance to equivalent ischemia/reperfusion injury indicated as no significant change from controls in any of these parameters. Tubular epithelial cells in transgenic mice expressed higher mitochondrial uncoupling protein 2 and lower superoxide generation. Pre-treatment of transgenic mice with paraquat, a generator of reactive oxygen species, before injury restored the susceptibility to ischemia/reperfusion kidney injury, suggesting that STC1 protects by an anti-oxidant mechanism. Thus, STC1 may be a therapeutic target for ischemia/reperfusion kidney injury.
活性氧、内皮功能障碍、炎症和丝裂原活化蛋白激酶在缺血/再灌注肾损伤的发病机制中起重要作用。促甲状腺激素释放激素 1（STC1）通过诱导线粒体解偶联蛋白抑制许多系统中超氧化物的产生，并阻止细胞因子诱导的内皮通透性增加。在这里，我们测试了 STC1 的转基因过表达是否能保护免受双侧缺血/再灌注肾损伤。这种在野生型小鼠中的损伤导致肌酐清除率减半；严重的肾小管空泡化和铸型形成；巨噬细胞和 T 细胞浸润增加；血管通透性增加；超氧化物和过氧化氢产生增加；以及激活的细胞外调节激酶/激活的 Jun-N-末端激酶和 p38 的比值更高，与假手术对照组相比均如此。然而，表达人 STC1 的转基因小鼠对等效的缺血/再灌注损伤具有抗性，这些参数中没有任何一个与对照组有显著变化。转基因小鼠的肾小管上皮细胞表达更高的线粒体解偶联蛋白 2 和更低的超氧化物生成。在损伤前用百草枯预处理转基因小鼠，一种活性氧的生成剂，恢复了对缺血/再灌注肾损伤的易感性，表明 STC1 通过抗氧化机制起保护作用。因此，STC1 可能是缺血/再灌注肾损伤的治疗靶点。
