title: NFAT5 contributes to osmolality-induced MCP-1 expression in mesothelial cells.
abstract: 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.
authors.affiliation: Department of Physiology, University of Munich, 80336 Munich, Germany. christoph.kueper@lrz.uni-muenchen.de
authors.forename: Christoph
authors.initials: C
authors.lastname: Küper
authors.forename: Franz-X
authors.initials: FX
authors.lastname: Beck
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Neuhofer
mesh_terms: D002460:Cell Line; D018932:Chemokine CCL2 / Q000096:biosynthesis*; D004847:Epithelial Cells / Q000166:cytology; D004848:Epithelium / Q000378:metabolism*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D007668:Kidney / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009994:Osmolar Concentration; D010531:Peritoneal Dialysis, Continuous Ambulatory / Q000379:methods; D014157:Transcription Factors / Q000096:biosynthesis* / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D016328:NF-kappa B; C118125:NFAT5 protein, human; D014157:Transcription Factors