Molecular Mechanisms of Peritoneal Fibrosis- Proteinkinase C alpha and Peritoneal Dialysis

• Applicant: Professor Dr. Hermann Haller
• Subject Area: Nephrology
• Term: since 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 284208194

In our previous experiments we were able to demonstrate in the experiments supported by that PKCα is the only classical PKC isoform expressed in MPMCs. PKCα protein expression and activation is upregulated in MPMCs in vitro under PD-simulating conditions and in vivo after prolonged exposure to PDF. Whereas in WT mice chronic PDF administration leads to severe morphologic, structural, and functional changes of the PM, the functional blockade of PKCα activity with Go6976 completely protected PM structure and function. PKCα deficiency showed a comparable benefit, suggesting a crucial role of PKCα in PM disturbances. Based on these findings in the last funding period we propose a novel therapeutic approach to prevent PD-fluid induced inflammation, neoangiogenesis and fibrosis. 1. Using an antisense strategy against PKC isoform alpha regularly applied with the PD fluid during dialysis we want to inhibit the glucose-induced inflammation, neoangiogenesis and fibrosis. The specific antisense approach prevents the side effects of other PKC inhibitors such as Gö, which may also affect multiple kinases from a variety of protein kinase families and usually have other pharmacological actions leading to different effects in vitro and in vivo independently from PKC inhibition. 2. We will analyze the therapeutic effect of our strategy on the different cell types of the peritoneum. We have evidence from our previous research that mesothelial cells are a main therapeutic target. However, we have also seen previously that PKC-a in endothelial cells, macrophages and fibroblasts plays an important role. We therefore plan to use single nucleus gene expression analysis to define our therapeutic strategy. be used in vivo, have a high specificity and can. The findings from these studies will allow us to identify the molecular and cellular mechanisms in the injured peritoneum which are addressed by our novel therapeutic strategy and to develop a targeted therapeutic approach using specific nanoparticles 3. To improve the pharmacokinetic and pharmacodynamic profile of of our antisense approach we will use nanoparticles. This approach will allow us to develop sophisticated targeting strategies and reduces the concentration of our antisense compound used.

• DFG Programme: Research Grants