AMPK dysregulation promotes diabetes-related reduction of superoxide and mitochondrial function
AMPK dysregulation promotes diabetes-related reduction of superoxide and mitochondrial function
复制标题
DOI：
10.1172/jci66218
复制
发表时间：
2013-11-01
影响因子：
15.9
通讯作者：
Sharma, Kumar
中科院分区：
文献类型：
--
作者：
Dugan, Laura L.;You, Young-Hyun;Sharma, Kumar
糖尿病微血管并发症被认为是由葡萄糖驱动的线粒体超氧阴离子产生增加介导的。在这里，我们报告说，通过体内实时经皮荧光、共聚焦显微镜和电子顺磁共振分析评估，在步脲佐菌素诱导的 1 型糖尿病小鼠模型中，肾脏中超氧化物的产生减少。在糖尿病小鼠的肾脏中观察到线粒体生物合成和丙酮酸脱氢酶（PDH）磷酸化的减少。这些观察结果与线粒体葡萄糖氧化的总体减少一致。 AMPK（主要的能量感应酶）的活性在糖尿病小鼠和人类的肾脏中均降低。使用 AMPK 激活剂 5-氨基咪唑-4-甲酰胺-1-β-D-呋喃核糖 (AICAR) 治疗可恢复线粒体生物发生、PDH 活性和线粒体复合物活性。 AICAR 治疗诱导超氧化物产生，并与糖尿病肾脏中肾小球基质和蛋白尿的减少有关。此外，糖尿病杂合超氧化物歧化酶2 (Sod(2+/-)) 小鼠没有肾脏疾病增加的证据，而Ampka(2-/-) 小鼠的白蛋白尿增加，但AICAR治疗并未减少这种情况。用鱼藤酮减少线粒体超氧化物的产生足以减少小鼠肾脏中的 AMPK 磷酸化。总而言之，这些结果表明糖尿病肾脏减少了超氧化物和线粒体的生物发生，并且 AMPK 的激活增强了超氧化物的产生和线粒体功能，同时降低了疾病活动性。
Diabetic microvascular complications have been considered to be mediated by a glucose-driven increase in mitochondrial superoxide anion production. Here, we report that superoxide production was reduced in the kidneys of a steptozotocin-induced mouse model of type 1 diabetes, as assessed by in vivo real-time transcutaneous fluorescence, confocal microscopy, and electron paramagnetic resonance analysis. Reduction of mitochondrial biogenesis and phosphorylation of pyruvate dehydrogenase (PDH) were observed in kidneys from diabetic mice. These observations were consistent with an overall reduction of mitochondrial glucose oxidation. Activity of AMPK, the major energy-sensing enzyme, was reduced in kidneys from both diabetic mice and humans. Mitochondrial biogenesis, PDH activity, and mitochond.rial complex activity were rescued by treatment with the AMPK activator 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranosicle (AICAR). AICAR treatment induced superoxide production and was linked with glomerular matrix and albuminuria reduction in the diabetic kidney. Furthermore, diabetic heterozygous superoxide dismutase 2 (Sod(2+/-)) mice had no evidence of increased renal disease, and Ampka(2-/-) mice had increased albuminuria that was not reduced with AICAR treatment. Reduction of mito chondrial superoxide production with rotenone was sufficient to reduce AMPK phosphorylation in mouse kidneys. Taken together, these results demonstrate that diabetic kidneys have reduced superoxide and mitochondrial biogenesis and activation of AMPK enhances superoxide production and mitochomirial function while reducing disease activity.