Abstract: SA-PO953
Systems Biology Analysis of Lithium-Mediated Cytoprotection in PD
Session Information
- Peritoneal Dialysis: Inflammation, Peritoneal Transport
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Dialysis
- 703 Dialysis: Peritoneal Dialysis
Authors
- Herzog, Rebecca, Medical University of Vienna, Vienna, Austria
- Gonzalez- Mateo, Guadalupe T., Molecular Biology Research Centre Severo Ochoa, Spanish Research Council, Madrid, Spain
- Bartosova, Maria, Center for Pediatric and Adolescent Medicine, Heidelberg, Germany
- Schmitt, Claus peter, Centre for Pediatric and Adolescent Medicine, Heidelberg, Germany
- Aufricht, Christoph, Medical University of Vienna, Vienna, Austria
- Kratochwill, Klaus, Medical University of Vienna, Vienna, Austria
Background
Peritoneal dialysis fluids (PDF) harm peritoneal cells, leading to transdifferentiation and cell death. Lithium chloride (LiCl), a clinically applicable kinase inhibitor, improved survival of immortalized mesothelial cells. Due to its availability and well-characterized pharmacological profile, LiCl could be a promising molecule to be used as local cytoprotective additive to PDF. The pleiotropic effects of LiCl on mesothelial cells, have not yet been investigated.
Methods
Here, we analyzed the protective potential of LiCl added to PDF in a systems biology approach which combined transcriptomics and proteomics analyses followed by validation in human samples and a chronic mouse model.
Results
PDF with LiCl caused significantly lower cell injury of primary human mesothelial cells in a dose dependent manner. PD-induced cell injury was associated with significantly differential expression of 478 genes and 92 proteins compared to control, LiCl in PDF altered 749 genes and 102 proteins. Pathway over-representation and molecular process enrichment tests showed a strong regulation of angiogenesis related pathways in response to PDF. Analysis of transcripts and proteins that were counter-regulated in PDF with LiCl compared to PDF alone, yielded candidates associated with the LiCl effect, with the small heat shock protein αB-crystallin as most strongly regulated candidate. αB-crystallin was significantly upregulated by PDF but close to control level with LiCl in the omics and targeted analyses. Modulated expression of αB-crystallin, which has been described as regulator of VEGF-mediated angiogenesis, confirmed its regulatory involvement in PD-induced pathomechanisms. Uremic as well as non-uremic mice showed significantly reduced peritoneal membrane thickening and transdifferentiation with LiCl. PDF-induced increased VEGF and αB-crystallin levels in peritoneal membranes were reduced with LiCl. The relevance was confirmed in significantly upregulated abundances of mesothelial αB-crystallin in biopsies from children treated with PD, compared to age-matched healthy controls or with CKD5.
Conclusion
The beneficial effects of LiCl in PDF may be explained by counter-regulation of the PD-induced angiogenesis via the novel target αB-crystallin. Reduction of cell damage and fibrosis suggests therapeutic potential of this intervention.