Protein kinase C beta deficiency increases glucose-mediated peritoneal damage via M1 macrophage polarization and up-regulation of mesothelial protein kinase C alpha

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 (PKC) isoform in mesothelial cells. Methods In this study we investigate the role of PKC in PM damage in vitro using primary mouse peritoneal macrophages (MPM), human macrophages (HM) and immortalized mouse peritoneal mesothelial cells (MPMCs), as well as in vivo using a chronic PD mouse model. Results We demonstrate that PKC is the predominant classical PKC isoform expressed in primary MPM phi and its expression is up-regulated in vitro under HG conditions. After in vitro lipopolysaccharides stimulation PKC-/- MPM phi demonstrates increased levels of interleukin 6 (IL-6), tumour necrosis factor , 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 5weeks induces PKC 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 PKC-/- animals. Underlying molecular mechanisms involve a pro-inflammatory M1 polarization shift of MPM phi and up-regulation of PKC in MPMCs of PKC-/- mice. Finally, we demonstrate PKC involvement in HG-induced polarization processes in HM phi. Conclusions PKC as the dominant PKC isoform in MPM phi is up-regulated by HG PD fluid and exerts anti-inflammatory effects during PD through regulation of MPM phi M1/M2 polarization and control of the dominant mesothelial PKC isoform alpha.