Indoxyl sulfate upregulates renal expression of MCP-1 via production of ROS and activation of NF-魏B, p53, ERK, and JNK in proximal tubular cells

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• 作者：Hidehisa Shimizu^a ; Dilinaer Bolati^a ; Yukihiro Higashiyama^b ; Fuyuhiko Nishijima^b ; Kazuya Shimizu^c ; Toshimitsu Niwa^a ; ^{tniwa@med.nagoya.u-ac.jp}
• 关键词：ROS ; NF-魏B ; p53 ; ERK ; p38 ; JNK ; Tubulointerstitial injury ; Chronic kidney disease
• 刊名：Life Sciences
• 出版年：2012
• 期刊代码：62_00243205
• 类别：imm
• 出版时间：9 April, 2012
• 卷：90
• 期：13-14
• 页码：525-530
• 文件大小：762 K

摘要

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-魏B and p53 in HK-2 cells. An antioxidant, and inhibitors of NF-魏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-魏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.