CKIP-1 ameliorates high glucose-induced expression of fibronectin and intercellular cell adhesion molecule-1 by activating the Nrf2/ARE pathway in glomerular mesangial cells
CKIP-1 ameliorates high glucose-induced expression of fibronectin and intercellular cell adhesion molecule-1 by activating the Nrf2/ARE pathway in glomerular mesangial cells
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CKIP-1通过激活肾小球系膜细胞中的Nrf2/ARE通路改善高糖诱导的纤连蛋白和细胞间细胞粘附分子-1的表达
DOI：
10.1016/j.bcp.2016.07.019
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发表时间：
2016-09-15
影响因子：
5.8
通讯作者：
Huang, Heqing
中科院分区：
文献类型：
--
作者：
Gong, Wenyan;Chen, Cheng;Huang, Heqing
糖脂代谢紊乱以及氧化应激（OSS）在糖尿病肾病（DN）中发挥重要作用。糖脂代谢紊乱是糖尿病慢性微血管并发症如DN的基本病理改变。OSS可导致细胞外基质和炎症因子的积聚，加速DN的进展。酪蛋白激酶2相互作用蛋白-1（CKIP-1）在许多情况下介导脂肪形成、细胞增殖和炎症。然而，CKIP-1是否参与DN的发展仍不清楚。CRIP-1是一种新的抗糖尿病肾病的调节因子，其机制与激活核因子E2相关因子2（Nrf 2）/抗氧化反应元件（ARE）抗氧化应激通路有关。结果发现：（1）高糖（HG）处理肾小球系膜细胞（GMCs）后，CKIP-1表达呈时间依赖性降低;（2）CKIP-1过表达显著降低纤维连接蛋白（FN）和细胞间粘附分子-1（ICAM-1）的表达。CKIP-1的缺失进一步诱导FN和ICAM-1的产生;（3）CKIP-1促进Nrf 2的核积累、DNA结合和转录活性。此外，CRIP-1上调Nrf 2下游基因、血红素加氧酶（HO-1）和超氧化物歧化酶1（SOD 1）的表达;并最终降低活性氧（ROS）水平。分子机制阐明GRIP-1对DN的有利作用与Nrf 2/ARE抗氧化应激通路的激活密切相关。(C)2016 Elsevier Inc. All rights reserved.
Glucose and lipid metabolism disorders as well as oxidative stress (OSS) play important roles in diabetic nephropathy (DN). Glucose and lipid metabolic dysfunctions are the basic pathological changes of chronic microvascular complications of diabetes mellitus, such as DN. OSS can lead to the accumulation of extracellular matrix and inflammatory factors which will accelerate the progress of DN. Casein kinase 2 interacting protein-1 (CKIP-1) mediates adipogenesis, cell proliferation and inflammation under many circumstances. However, whether CKIP-1 is involved in the development of DN remains unknown. Here, we show that CRIP-1 is a novel regulator of resisting the development of DN and the underlying molecular mechanism is related to activating the nuclear factor E2-related factor 2 (Nrf2)/antioxidant response element (ARE) antioxidative stress pathway. The following findings were obtained: (1) The treatment of glomerular mesangial cells (GMCs) with high glucose (HG) decreased CKIP-1 levels in a time-dependent manner; (2) CKIP-1 overexpression dramatically reduced fibronectin (FN) and intercellular adhesionmolecule-1 (ICAM-1) expression. Depletion of CKIP-1 further induced the production of FN and ICAM-1; (3) CKIP-1 promoted the nuclear accumulation, DNA binding, and transcriptional activity of Nrf2. Moreover, CRIP-1 upregulated the expression of Nrf2 downstream genes, heme oxygenase (HO-1) and superoxide dismutase 1 (SOD1); and ultimately decreased the levels of reactive oxygen species (ROS). The molecular mechanisms clarify that the advantageous effect of GRIP-1 on DN are well connected with the activation of the Nrf2/ARE antioxidative stress pathway. (C) 2016 Elsevier Inc. All rights reserved.