Reduction of Renal Superoxide Dismutase in Progressive Diabetic Nephropathy
Reduction of Renal Superoxide Dismutase in Progressive Diabetic Nephropathy
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DOI：
10.1681/asn.2008080844
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发表时间：
2009-06-01
影响因子：
13.6
通讯作者：
Takahashi, Takamune
中科院分区：
文献类型：
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作者：
Fujita, Hiroki;Fujishima, Hiromi;Takahashi, Takamune
超氧化物在糖尿病引起的组织损伤中起着重要作用，但超氧化物在糖尿病肾病（DN）中的机制尚不完全清楚。在本研究中，我们调查了酶超氧化物歧化酶（SOD），一个主要的防御超氧化物，在肾脏中的发展过程中，小鼠DN。我们评估了两种糖尿病小鼠模型（C57 BL/6-秋田和KK/Ta-秋田）肾脏中SOD活性和SOD亚型的表达，这两种模型表现出相当的高血糖水平，但对DN的易感性不同。我们观察到在呈现进行性DN的KK/Ta-Akita小鼠的肾脏中，细胞溶质CuZn-SOD（SOD 1）和细胞外CuZn-SOD（SOD 3）下调，但线粒体Mn-SOD（SOD 2）未下调。与此相反，我们没有检测到肾脏SOD的表达在DN耐药的C57 BL/6-秋田小鼠的变化。与这些发现一致，与C57 BL/6-秋田小鼠相比，KK/Ta-秋田小鼠肾脏中总SOD活性显著降低。最后，用SOD模拟物tempol治疗KK/Ta-Akita小鼠，在不改变高血糖水平的情况下改善了KK/Ta-Akita小鼠的肾病变化。总之，这些结果表明，肾脏SOD 1和SOD 3的下调可能在DN的发病机制中起关键作用。
Superoxide excess plays a central role in tissue damage that results from diabetes, but the mechanisms of superoxide overproduction in diabetic nephropathy (DN) are incompletely understood. In the present study, we investigated the enzyme superoxide dismutase (SOD), a major defender against superoxide, in the kidneys during the development of murine DN. We assessed SOD activity and the expression of SOD isoforms in the kidneys of two diabetic mouse models (C57BL/6-Akita and KK/Ta-Akita) that exhibit comparable levels of hyperglycemia but different susceptibility to DN. We observed down-regulation of cytosolic CuZn-SOD (SOD1) and extracellular CuZn-SOD (SOD3), but not mitochondrial Mn-SOD (SOD2), in the kidney of KK/Ta-Akita mice which exhibit progressive DN. In contrast, we did not detect a change in renal SOD expression in DN-resistant C57BL/6-Akita mice. Consistent with these findings, there was a significant reduction in total SOD activity in the kidney of KK/Ta-Akita mice compared with C57BL/6-Akita mice. Finally, treatment of KK/Ta-Akita mice with a SOD mimetic, tempol, ameliorated the nephropathic changes in KK/Ta-Akita mice without altering the level of hyperglycemia. Collectively, these results indicate that down-regulation of renal SOD1 and SOD3 may play a key role in the pathogenesis of DN.