Indoxyl sulfate upregulates renal expression of MCP-1 via production of ROS and activation of NF-κB, p53, ERK, and JNK in proximal tubular cells
Indoxyl sulfate upregulates renal expression of MCP-1 via production of ROS and activation of NF-κB, p53, ERK, and JNK in proximal tubular cells
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DOI：
10.1016/j.lfs.2012.01.013
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发表时间：
2012-04-09
期刊：
影响因子：
6.1
通讯作者：
Niwa, Toshimitsu
中科院分区：
文献类型：
--
作者：
Shimizu, Hidehisa;Bolati, Dilinaer;Niwa, Toshimitsu
目的：单核细胞趋化蛋白-1（MCP-1）在募集单核细胞/巨噬细胞到损伤的肾小管间质组织中起重要作用。本研究旨在探讨硫酸吲哚酚（indoxyl sulfate）对肾组织MCP-1表达的影响。主要方法：采用人近端肾小管上皮细胞，观察硫酸吲哚酚对肾组织MCP-1表达的影响（HK-2细胞）和以下动物：（1）Dahl盐抗性血压正常大鼠（DN），（2）Dahl盐抗性血压正常硫酸吲哚酚给药大鼠（DN + IS），（3）Dahl盐敏感性高血压大鼠（DH）和（4）Dahl盐敏感性高血压硫酸吲哚酚给药大鼠（DH + IS）。关键发现：与DN大鼠相比，DN + IS、DH和DH + IS大鼠肾脏中MCP-1 mRNA表达显著增加。与DH大鼠相比，DH + IS大鼠肾脏中MCP-1的mRNA表达倾向于增加。免疫组织化学显示硫酸吲哚酚对肾脏中MCP-1表达和单核细胞/巨噬细胞浸润的刺激作用。硫酸吲哚酚可上调HK-2细胞MCP-1的mRNA和蛋白表达。硫酸吲哚酚诱导HK-2细胞中ERK、p38和JNK以及NF-κ B和p53的活化。一种抗氧化剂、NF-κ B B、p53、ERK通路（MEK 1/2）和JNK抑制剂抑制了硫酸吲哚酚诱导的HK-2细胞MCP-1 mRNA表达。意义：硫酸吲哚酚通过产生活性氧（ROS）和激活近端肾小管细胞中的NF-κ B、p53、ERK和JNK上调MCP-1的肾表达。因此，硫酸吲哚酚在慢性肾脏疾病中的积累可能通过诱导肾脏中的MCP-1而参与肾小管间质损伤的发病机制。(C)2012 Elsevier Inc. All rights reserved.
Aims: Monocyte chemotactic protein-1 (MCP-1) plays an important role in recruiting monocytes/macrophages to injured tubulointerstitial tissue. The present study examined whether indoxyl sulfate, a uremic toxin, regulates renal expression of MCP-1.Main methods: The effect of indoxyl sulfate on the expression of MCP-1 was determined using human proximal tubular cells (HK-2 cells) and following animals: (1) Dahl salt-resistant normotensive rats (DN), (2) Dahl salt-resistant normotensive indoxyl sulfate-administered rats (DN + IS), (3) Dahl salt-sensitive hypertensive rats (DH), and (4) Dahl salt-sensitive hypertensive indoxyl sulfate-administered rats (DH + IS).Key findings: DN + IS, DH, and DH + IS rats showed significantly increased mRNA expression of MCP-1 in the kidneys compared with DN rats. DH + IS rats tended to show increased mRNA expression of MCP-1 in the kidneys compared with DH rats. Immunohistochemistry demonstrated the stimulatory effects of indoxyl sulfate on MCP-1 expression and monocyte/macrophage infiltration in the kidneys. Indoxyl sulfate upregulated mRNA and protein expression of MCP-1 in HK-2 cells. Indoxyl sulfate induced activation of ERK, p38, and JNK as well as of NF-kappa B and p53 in HK-2 cells. An antioxidant, and inhibitors of NF-kappa B, p53, ERK pathway (MEK1/2), and JNK suppressed indoxyl sulfate-induced mRNA expression of MCP-1 in HK-2 cells.Significance: Indoxyl sulfate upregulates renal expression of MCP-1 through production of reactive oxygen species (ROS), and activation of NF-kappa B, p53, ERK, and JNK in proximal tubular cells. Thus, accumulation of indoxyl sulfate in chronic kidney disease might be involved in the pathogenesis of tubulointerstitial injury through induction of MCP-1 in the kidneys. (C) 2012 Elsevier Inc. All rights reserved.