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Abstract: PO2047

Multi-Omics Analysis Reveals Regulatory Mechanisms in Chronic Cyclosporine A-Induced Nephrotoxicity Studied in a Rat Model

Session Information

Category: Transplantation

  • 1901 Transplantation: Basic

Authors

  • Demirci, Hasan, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Yilmaz, Duygu Elif, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Popovic, Suncica, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Hu, Junda, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Mutig, Kerim, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Bachmann, Sebastian, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
Background

Chronic calcineurin inhibitor (CNI) nephrotoxicity is a major drawback in current immunosuppressive regimens. In the chronic setting, arteriolar hyalinosis, decreased glomerular filtration rate, interstitial fibrosis and tubular dedifferentiation are the major adverse side effects. Regimens with cyclosporine A (CsA) and tacrolimus (Tac) have been compared before the background of potentially more harmful effects of CsA. Conversely, CsA is still widely used in transplant recipients and has been considered for replacement of Tac in posttransplant diabetes.To identify regulatory mechanisms in CsA nephrotoxicity we used quantitative transcriptomic, proteomic and phosphoproteomic methods. We tested the hypothesis that tubulointerstitial pathomechanisms play a significant role in chronic CNI nepropathy.

Methods

Whole transciptome RNA-seq as well as global proteomic and phosphoproteomic methodologies were performed on kidney extracts from normal Wistar rats receiving CsA (25mg/kg b.w./day) or vehicle for 3 weeks. Differentially expressed genes and proteins as well as their phosphorylation status were obtained.

Results

CsA treatment stimulated genome-wide alterations in rat kidney according to the RNA-seq data. We identified 342 transcripts upregulated which included Ribosome and Oxidative phosphorylation pathways, whereas 331 transcripts were downregulated, with enrichment in genes critical for amino acid metabolism. Data were controlled by the established upregulation of renin and downregulation of calbindin in global proteomics. KEGG pathway and GO analysis from proteomics largely corresponded to the RNA-seq results. Upregulated proteins were further related to ECM-receptor interaction and focal adhesion pathways (padj<0,05). Phosphoproteomics demonstrated functional phosphorylation of components from unfolded protein response pathways, indicating an activation of the integrated stress response upon CsA.

Conclusion

In sum, using integrated -omics analysis in CsA nephrotoxicity proves to be a powerful approach. Chronic CsA treatment is associated with enhanced energy metabolism and activation of the unfolded protein-response pathways. A tubulointerstitial focus has been demonstrated. Potential biomarker candidates have further been obtained and are currently verified in the rat model.