scholarly journals NFAT5 Contributes to Osmolality-Induced MCP-1 Expression in Mesothelial Cells

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Christoph Küper ◽  
Franz-X. Beck ◽  
Wolfgang Neuhofer

Increased expression of the C-C chemokine monocyte chemoattractant protein-1 (MCP-1) in mesothelial cells in response to high glucose concentrations and/or high osmolality plays a crucial role in the development of peritoneal fibrosis during continuous ambulatory peritoneal dialysis (CAPD). Recent studies suggest that in kidney cells osmolality-induced MCP-1 upregulation is mediated by the osmosensitive transcription factor, nuclear factor of activated T cells 5 (NFAT5). The present study addressed the question of whether activation of NFAT5 by hyperosmolality, as present in PD fluids, contributes to MCP-1 expression in the mesothelial cell line Met5A. Hyperosmolality, induced by addition of glucose, NaCl, or mannitol to the growth medium, increased NFAT5 activity and stimulated MCP-1 expression in Met5A cells. siRNA-mediated knockdown of NFAT5 attenuated osmolality-induced MCP-1 upregulation substantially. Hyperosmolality also induced activation of nuclear factor-κB (NF-κB). Accordingly, pharmacological inhibition of NF-κB significantly decreased osmolality-induced MCP-1 expression. Taken together, these results indicate that high osmolalities activate the transcription factor NFAT5 in mesothelial cells. NFAT5 in turn upregulates MCP-1, likely in combination with NF-κB, and thus may participate in the development of peritoneal fibrosis during CAPD.

Diabetes ◽  
2006 ◽  
Vol 55 (5) ◽  
pp. 1450-1455 ◽  
Author(s):  
B. Yang ◽  
A. D. Hodgkinson ◽  
P. J. Oates ◽  
H. M. Kwon ◽  
B. A. Millward ◽  
...  

2002 ◽  
Vol 13 (4) ◽  
pp. 894-902 ◽  
Author(s):  
Hunjoo Ha ◽  
Mi Ra Yu ◽  
Yoon Jin Choi ◽  
Masanori Kitamura ◽  
Hi Bahl Lee

ABSTRACT. Although high glucose (HG) has been shown to induce nuclear factor-κB (NF-κB) activation in vascular cells, the upstream regulation and the biologic significance of NF-κB activation in diabetic renal injury are not clear. It was, therefore, examined if HG-induced generation of reactive oxygen species (ROS) and protein kinase C (PKC) activation are involved in NF-κB activation in mesangial cells (MC), and the role of NF-κB activation in HG-induced monocyte chemoattractant protein-1 (MCP-1) expression by MC was further investigated. Recent observations suggest that MCP-1 may play a role in the development and progression of diabetic nephropathy. HG rapidly induced NF-κB activation in MC as estimated by electrophoretic mobility shift assay. Supershift assay suggests that most of the binding activity arose from p50/p50 and p50/p65 dimers. Antioxidants, pyrrolidine dithiocarbamate, n-acetyl-l-cystein, and trolox effectively inhibited HG-induced NF-κB activation in MC. HG rapidly generated dichlorofluorescin-sensitive intracellular ROS in MC as measured by laser-scanning confocal microscopy. HG also activated PKC rapidly in MC. Inhibition of PKC effectively blocked HG-induced intracellular ROS generation and NF-κB activation in MC. HG increased MCP-1 mRNA expression by 1.9-fold and protein secretion by 1.6-fold that of control glucose in MC transfected with control vector but not in MC transfected with dominant negative mutant inhibitor of NF-κB (IκBαM). Inhibition of either PKC or ROS effectively blocked HG-induced, but not basal, MCP-1 protein secretion by MC transfected with control vector. Thus this study demonstrates that HG rapidly activates NF-κB in MC through PKC and ROS and suggests that HG-induced NF-κB activation in MC may play a role in diabetic renal injury through upregulation of MCP-1 mRNA and protein expression.


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