| First Author | Balzer MS | Year | 2019 |
| Journal | Nephrol Dial Transplant | Volume | 34 |
| Issue | 6 | Pages | 947-960 |
| PubMed ID | 30247663 | Mgi Jnum | J:319323 |
| Mgi Id | MGI:6863693 | Doi | 10.1093/ndt/gfy282 |
| Citation | Balzer MS, et al. (2019) Protein kinase C beta deficiency increases glucose-mediated peritoneal damage via M1 macrophage polarization and up-regulation of mesothelial protein kinase C alpha. Nephrol Dial Transplant 34(6):947-960 |
| abstractText | 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 alpha in mesothelial cells. METHODS: In this study we investigate the role of PKCbeta in PM damage in vitro using primary mouse peritoneal macrophages (MPMPhi), human macrophages (HMPhi) and immortalized mouse peritoneal mesothelial cells (MPMCs), as well as in vivo using a chronic PD mouse model. RESULTS: We demonstrate that PKCbeta is the predominant classical PKC isoform expressed in primary MPMPhi and its expression is up-regulated in vitro under HG conditions. After in vitro lipopolysaccharides stimulation PKCbeta-/- MPMPhi demonstrates increased levels of interleukin 6 (IL-6), tumour necrosis factor alpha, 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 5 weeks induces PKCbeta 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 PKCbeta-/- animals. Underlying molecular mechanisms involve a pro-inflammatory M1 polarization shift of MPMPhi and up-regulation of PKCalpha in MPMCs of PKCbeta-/- mice. Finally, we demonstrate PKCbeta involvement in HG-induced polarization processes in HMPhi. CONCLUSIONS: PKCbeta as the dominant PKC isoform in MPMPhi is up-regulated by HG PD fluid and exerts anti-inflammatory effects during PD through regulation of MPMPhi M1/M2 polarization and control of the dominant mesothelial PKC isoform alpha. |
