[No authors listed]
BACKGROUND:Peritoneal membrane (PM) damage during peritoneal dialysis (PD) is mediated largely by high glucose (HG)-induced pro-inflammatory and neo-angiogenic processes, resulting in PM fibrosis and ultrafiltration failure. We recently demonstrated a crucial role for protein kinase C isoform α in mesothelial cells. METHODS:In this study we investigate the role of in PM damage in vitro using primary mouse peritoneal macrophages (MPMΦ), human macrophages (HMΦ) and immortalized mouse peritoneal mesothelial cells (MPMCs), as well as in vivo using a chronic PD mouse model. RESULTS:We demonstrate that duanyu1531β is the predominant classical isoform expressed in primary MPMΦ and its expression is up-regulated in vitro under HG conditions. After in vitro lipopolysaccharides stimulation MPMΦ demonstrates increased levels of interleukin 6 (IL-6), tumour necrosis factor α, and monocyte chemoattractant protein-1 and drastically decrease IL-10 release compared with wild-type (WT) cells. In vivo, catheter-delivered treatment with HG PD fluid for 5âweeks induces duanyu1531β up-regulation in omentum of WT mice and results in inflammatory response and PM damage characterized by fibrosis and neo-angiogenesis. In comparison to WT mice, all pathological changes are strongly aggravated in duanyu1531β-/- animals. Underlying molecular mechanisms involve a pro-inflammatory M1 polarization shift of MPMΦ and up-regulation of in MPMCs of duanyu1531β-/- mice. Finally, we demonstrate duanyu1531β involvement in HG-induced polarization processes in as the dominant duanyu1531 isoform in MPMΦ is up-regulated by HG PD fluid and exerts anti-inflammatory effects during PD through regulation of MPMΦ M1/M2 polarization and control of the dominant mesothelial duanyu1531 isoform α.
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