Proteomische Analyse der Nephrotoxizität im Falle der Cyclosporin A und Tacrolimus Therapie

by Hauke Sebastian Wülfrath
Doctoral thesis
Date of Examination:2023-05-03
Date of issue:2023-05-03
Advisor:Prof. Dr. Hassan Dihazi
Referee:Prof. Dr. Hassan Dihazi
Referee:Prof. Dr. Henning Urlaub
Persistent Address: http://dx.doi.org/10.53846/goediss-9869

 

 

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Abstract

English

Immunosuppressants have made organ transplantation possible as a therapeutic intervention. One of the first and still most important groups of drugs among immunosuppressants are the calcineurin inhibitors, including Cyclosporin A and Tacrolimus. Nephrotoxicity of calcineurin inhibitors as an undesirable drug effect occurs both acutely and chronically. Calcineurin inhibitor nephrotoxicity is often dose-limiting in therapy. Renal fibrosis plays an important role in chronic calcineurin inhibitor nephrotoxicity. Renal fibrosis in general is largely mediated by endoplasmic reticulum stress. Among others, the proteins GRP78, ERP57, and Calreticulin regulate this stress. Cyclosporin A and Tacrolimus exhibit toxic effects on the renal cell lines HK-2 and TK-173 at micromolar concentrations. This toxic effect is manifested by reduced cell viability and increased apoptosis rate of the cells, accompanied by increased expression of ER stress proteins. In this study, for the first time, a proteomic analysis of the nephrotoxicity of calcineurin inhibitors on HK-2 cells was conducted. Regulated signaling pathways were identified that are known to contribute to kidney pathologies and may serve as potential targets for therapeutic interventions to alleviate calcineurin inhibitor nephrotoxicity. The increased expression of ER stress proteins leads to increased tolerance of HK-2 cells to Cyclosporin A and Tacrolimus. At the same time, reduced expression of the same ER stress proteins results in decreased tolerance to calcineurin inhibitors. This suggests a protective effect of ER stress proteins against the toxic effects of calcineurin inhibitors on renal cell lines.
Keywords: calcineurin inhibitor; transplantation; proteomics; endoplasmic reticulum stress
 
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