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

Abstract EN

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.