Journal Article

Acidic stress–ER stress axis for blunted activation of NF-κB in mesothelial cells exposed to peritoneal dialysis fluid

Hisashi Johno, Ryouji Ogata, Shotaro Nakajima, Nobuhiko Hiramatsu, Tetsuro Kobayashi, Hideaki Hara and Masanori Kitamura

in Nephrology Dialysis Transplantation

Published on behalf of European Renal Association - European Dialysis and Transplant Assoc

Volume 27, issue 11, pages 4053-4060
Published in print November 2012 | ISSN: 0931-0509
Published online May 2012 | e-ISSN: 1460-2385 | DOI: http://dx.doi.org/10.1093/ndt/gfs130
Acidic stress–ER stress axis for blunted activation of NF-κB in mesothelial cells exposed to peritoneal dialysis fluid

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Background

Bacterial peritonitis is a frequent complication in patients on peritoneal dialysis (PD). We previously reported that PD fluid (PDF) suppressed expression of monocyte chemoattractant protein 1 (MCP-1) in mesothelial cells in vitro and in vivo, which was ascribed to the suppression of nuclear factor-κB (NF-κB). To elucidate molecular mechanisms underlying this effect, we tested a role of endoplasmic reticulum (ER) stress.

Methods

Mesothelial cells and other cell types were exposed to acidic stress, and induction of the unfolded protein response was examined. Peritoneal induction of ER stress was also tested in mice exposed to acidic and neutralized PDF. Activation of NF-κB and expression of MCP-1 by tumour necrosis factor-α were evaluated in mesothelial cells under acidic and ER stress conditions. Peritoneal expression of MCP-1 and infiltration of monocytes were compared in lipopolysaccharide (LPS)-treated mice between normal and ER stress conditions.

Results

PDF, but not neutralized PDF, caused ER stress in the peritoneum. In vitro, acidic stress, but not metabolic and osmotic stress, induced ER stress in mesothelial cells and other cell types and suppressed activation of NF-κB and NF-κB-dependent MCP-1 induction. This effect was reproducible by other ER stress inducers, and attenuation of ER stress reversed the suppressive effect of low pH on NF-κB. Like PDF, ER stress inducers suppressed expression of MCP-1 and infiltration of mononuclear cells in the peritoneum of LPS-treated mice.

Conclusion

These results indicate a role for the acidic stress–ER stress pathway in blunted activation of NF-κB, which may cause perturbation of monocyte recruitment by mesothelial cells in PD patients.

Keywords: acidic stress; ER stress; MCP-1; mesothelial cell; NF-κB

Journal Article.  4525 words.  Illustrated.

Subjects: Nephrology

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