miR-451 suppresses the NF-kappaB-mediated proinflammatory molecules expression through inhibiting LMP7 in diabetic nephropathy
miR-451 suppresses the NF-kappaB-mediated proinflammatory molecules expression through inhibiting LMP7 in diabetic nephropathy
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DOI：
10.1016/j.mce.2016.06.004
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发表时间：
2016-09-15
影响因子：
4.1
通讯作者：
Zhang, Zheng
中科院分区：
文献类型：
--
作者：
Sun, Yan;Peng, Rui;Zhang, Zheng
核因子-κ B（NF-κ B）的活化与糖尿病肾病（DN）进展中的炎症相关。MiR-451与DN中的肾损害密切相关。大的多功能蛋白酶7（LMP 7）是一种免疫蛋白酶体亚基，可以激活NF-κ B。然而，目前尚不清楚miR-451是否通过调节DN中的LMP7来影响NF-κ B诱导的炎症。本研究分别采用了深度测序、原位杂交、实时荧光定量PCR、双荧光素酶报告基因检测、蛋白质印迹和染色质免疫沉淀等技术。对于结果，我们发现miR-451在db/db小鼠的肾脏、DN患者的PBMC和高糖条件下培养的系膜细胞（MCs）中显著下调。此外，miR-451直接靶向LMP7表达以抑制NF-κ B活性，并下调MC中促炎分子的转录。更重要的是，在db/db DN小鼠的肾脏中，增加miR-451水平抑制LMP7/NF-κ B活性，并减轻尿微量白蛋白排泄、血糖和肾小球损伤。总之，这些结果提供了新的见解，通过LMP7/NF-κ B中枢炎症通路在DN的进展过程中的miR-451的调节。(C)2016爱思唯尔爱尔兰有限公司版权所有。
Activation of nuclear factor-kappa B (NF-kappa B) is associated with inflammation in the progression of diabetic nephropathy (DN). MiR-451 is closely linked to renal damage in DN. Large multifunctional protease 7 (LMP7), an immunoproteasome subunit, can activate NF-kappa B. However, it remained unclear whether miR-451 affected NF-kappa B-induced inflammation by regulating LMP7 in DN. In this study, deep sequencing, in situ hybridization, quantitative real-time PCR, dual-luciferase reporter gene assays, western blot and chromatin immunoprecipitation were respectively used. For the results, we found that miR-451 was markedly downregulated in the kidneys of db/db mice, PBMCs of DN patients and mesangial cells (MCs) cultured in high glucose conditions. Furthermore, miR-451 directly targeted LMP7 expression to inhibit NF-kappa B activity, and down-regulated transcription of proinflammatory molecules in MCs. More importantly, in the kidneys of db/db DN mice, increasing miR-451 level inhibited LMP7/NF-kappa B activity, and attenuated the urinary microalbumin excretion, blood glucose, and glomerular injury. In conclusion, these results provide new insights into the regulation of miR-451 via the LMP7/NF-kappa B central inflammatory pathway during progression of DN. (C) 2016 Elsevier Ireland Ltd. All rights reserved.