RAGE deficiency improves postinjury sciatic nerve regeneration in type 1 diabetic mice.
RAGE deficiency improves postinjury sciatic nerve regeneration in type 1 diabetic mice.
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DOI：
10.2337/db12-0632
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发表时间：
2013-03
期刊：
影响因子：
7.7
通讯作者：
Schmidt AM
中科院分区：
文献类型：
--
作者：
Juranek JK;Geddis MS;Song F;Zhang J;Garcia J;Rosario R;Yan SF;Brannagan TH;Schmidt AM
周围神经病变和麻木的四肢和手指导致糖尿病患者的显著发病率。先前的研究表明，小鼠晚期糖基化终末产物受体（receptor for advanced end-glycation products，EDP）的缺失对长期糖尿病神经病变具有保护作用。在这里，我们测试的假设，在叠加急性周围神经损伤可归因于组织损伤炎症反应的轴突再生抑制有效。我们报告说，删除的ESTA，特别是在糖尿病小鼠，导致显着更高的有髓纤维密度和传导速度随之而来的急性坐骨神经挤压与野生型对照动物相比。与RAGE依赖性炎症的关键作用一致，用RAGE-无效与野生型骨髓重建糖尿病野生型小鼠导致轴突再生和功能恢复显著改善。与野生型动物相比，糖尿病RAGE基因敲除小鼠在挤压后的神经节段中显示出更高数量的侵入巨噬细胞，并且糖尿病RAGE基因敲除小鼠中的这些巨噬细胞显示出更大的M2极化。在体外，用在糖尿病神经组织中积累的晚期糖基化终产物（AGEs）处理野生型骨髓源性巨噬细胞，以RAGE依赖性方式增加M1基因表达并降低M2基因表达。通过上调再生信号，阻断β-淀粉样蛋白可能对糖尿病神经病变的急性并发症有益，至少部分是有益的。
Peripheral neuropathy and insensate limbs and digits cause significant morbidity in diabetic individuals. Previous studies showed that deletion of the receptor for advanced end-glycation products (RAGE) in mice was protective in long-term diabetic neuropathy. Here, we tested the hypothesis that RAGE suppresses effective axonal regeneration in superimposed acute peripheral nerve injury attributable to tissue-damaging inflammatory responses. We report that deletion of RAGE, particularly in diabetic mice, resulted in significantly higher myelinated fiber densities and conduction velocities consequent to acute sciatic nerve crush compared with wild-type control animals. Consistent with key roles for RAGE-dependent inflammation, reconstitution of diabetic wild-type mice with RAGE-null versus wild-type bone marrow resulted in significantly improved axonal regeneration and restoration of function. Diabetic RAGE-null mice displayed higher numbers of invading macrophages in the nerve segments postcrush compared with wild-type animals, and these macrophages in diabetic RAGE-null mice displayed greater M2 polarization. In vitro, treatment of wild-type bone marrow–derived macrophages with advanced glycation end products (AGEs), which accumulate in diabetic nerve tissue, increased M1 and decreased M2 gene expression in a RAGE-dependent manner. Blockade of RAGE may be beneficial in the acute complications of diabetic neuropathy, at least in part, via upregulation of regeneration signals.
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影响因子：
7.7
作者：
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