Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan.
Nephrol Dial Transplant. 2012 Nov;27(11):4053-60. doi: 10.1093/ndt/gfs130. Epub 2012 May 9.
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.
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.
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.
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.
细菌性腹膜炎是腹膜透析（PD）患者常见的并发症。我们之前报道 PD 液（PDF）在体外和体内均能抑制间皮细胞中单核细胞趋化蛋白 1（MCP-1）的表达，这归因于核因子-κB（NF-κB）的抑制。为了阐明这种作用的分子机制，我们测试了内质网（ER）应激的作用。
将间皮细胞和其他细胞类型暴露于酸性应激下，检测未折叠蛋白反应的诱导情况。还在暴露于酸性和中性 PDF 的小鼠中测试了腹膜 ER 应激的诱导。在酸性和 ER 应激条件下，评估了肿瘤坏死因子-α（TNF-α）对 NF-κB 的激活和 MCP-1 的表达。在正常和 ER 应激条件下，比较 LPS 处理的小鼠腹膜中 MCP-1 的表达和单核细胞的浸润。
PDF 但不是中性 PDF 引起腹膜 ER 应激。在体外，酸性应激而不是代谢和渗透应激诱导间皮细胞和其他细胞类型的 ER 应激，并抑制 NF-κB 的激活和 NF-κB 依赖性 MCP-1 的诱导。其他 ER 应激诱导剂也产生了这种效应，而 ER 应激的减轻逆转了低 pH 对 NF-κB 的抑制作用。与 PDF 一样，ER 应激诱导剂也抑制了 LPS 处理的小鼠腹膜中 MCP-1 的表达和单核细胞的浸润。
这些结果表明酸性应激-ER 应激途径在 NF-κB 激活减弱中起作用，这可能导致 PD 患者间皮细胞募集单核细胞的紊乱。
