Abstract: SA-PO714

Protein Kinase C Isoforms Alpha and Beta Are Differentially Regulated in Glucose-Mediated In Vivo and In Vitro Peritoneal Dialysis

Session Information

  • Peritoneal Dialysis - II
    November 04, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Dialysis

  • 608 Peritoneal Dialysis

Authors

  • Balzer, Michael S., Hannover Medical School , Hannover, Germany
  • Von Vietinghoff, Sibylle, Hannover Medical School , Hannover, Germany
  • Kiyan, Yulia, Hannover Medical School , Hannover, Germany
  • Haller, Hermann G., Hannover Medical School , Hannover, Germany
  • Shushakova, Nelli, Hannover Medical School , Hannover, Germany
Background

Damage to the peritoneal membrane (PM) during peritoneal dialysis (PD) comprises inflammatory, neoangiogenetic and fibrotic processes. In a PD mouse model, we have previously demonstrated glucose-mediated pro-inflammatory, pro-fibrotic and pro-angiogenic properties of protein kinase C (PKC)-alpha, which is the dominant mesothelial PKC isoform. Preliminary data suggest regulation of PKC-alpha by PKC-beta at the PM. The specific role of PKC-beta and especially its main source in glucose-mediated PM damage are not clear.

Methods

For in vivo PD, PKC-beta KO and WT mice were subjected to a catheter-delivered, high glucose-mediated PM damage model (once daily with 4.25% glucose for 5 weeks) and analyzed for structural and functional PM changes. Peritoneal effluents were analyzed for cellular and cytokine composition. PKC-beta expression was analyzed in omentum, mesothelial cells and macrophages of WT animals. For in vitro PD, both immortalized mouse peritoneal mesothelial cells (MPMC) and primary mouse peritoneal macrophages were stimulated with different glucose concentrations and studied for cytokine and PKC expression.

Results

In comparison to WT mice, PKC-beta KO mice undergoing PD demonstrated a stronger fibrotic and angiogenetic phenotype with higher peritoneal TGF-beta production, larger fibrotic areas and increased peritoneal VEGF and CD31 expression. PKC-beta deficiency in vivo increased peritoneal IL-6, TNF-alpha, MCP-1 and MIP-2 levels as well as PM inflammatory cell influx. In contrast to mesothelium, PKC-beta is the predominant conventional PKC isoform in peritoneal macrophages, which was further up-regulated by high glucose. After LPS stimulation PKC-beta KO peritoneal macrophages demonstrated increased production of pro-inflammatory cytokines IL-6, TNF-alpha and MCP-1 and drastically decreased production of anti-inflammatory cytokine IL-10 compared to WT cells.

Conclusion

PKC-beta, the dominant mesothelial PKC isoform in peritoneal macrophages, is up-regulated and exerts peritoneal anti-inflammatory effects during PD through regulation of the dominant mesothelial PKC isoform PKC-alpha. PKC-beta deficient animals present a macrophage phenotype in response to in vivo PD.