Major pathways of polymyxin-induced apoptosis in rat kidney proximal tubular cells
- Details
- Publication Year 2015-04,Volume 59,Issue #4,Page 2136-43
- Journal Title
- Antimicrob Agents Chemother
- Publication Type
- Journal Article
- Abstract
- Identifying the pathways involved in the apoptotic cell death that is associated with polymyxin-induced nephrotoxicity is crucial for the development of strategies to ameliorate this dose-limiting side-effect and for the development of novel safer polymyxins. The primary aim of this study is to identify the major pathways which lead to polymyxin-induced apoptosis in cultured rat kidney proximal tubular cells (NRK-52E). Caspase-3, 8 and 9 were activated by polymyxin B treatment in a concentration-dependent manner. Concentration- and time-dependent expression of FasL and deformation of mitochondrial morphology were revealed following polymyxin B treatment. The percentage of cells with filamentous mitochondria (regular morphology) following 8-h treatment with 1.0 mM polymyxin B was 56.2 +/- 9.7% (n = 3). This was decreased to 30.7 +/- 7.5% when the polymyxin B concentration was increased to 2.0 mM polymyxin B. The mitochondrial membrane potential (Deltapsim) decreased to 14.1 +/- 2.9% in the cells treated with 1.0 mM polymyxin B for 24 h (n = 3), compared to that in the untreated control group. Concomitantly, concentration- and time-dependent production of mitochondrial superoxide was also observed. This study is the first to demonstrate that polymyxin-induced apoptosis is mediated through both death receptor and mitochondrial pathways in cultured renal tubular cells. It provides key information not only for the amelioration of polymyxin-induced nephrotoxicity but also for the discovery of novel safer polymyxin-like antibiotics against Gram-negative 'superbugs'.
- Publisher
- American Society for Microbiology
- Research Division(s)
- Systems Biology And Personalised Medicine
- PubMed ID
- 25624331
- Link To PubMed Central Version
- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4356794/
- Publisher's Version
- https://doi.org/10.1128/AAC.04869-14
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2015-02-05 03:45:50
Last Modified: 2015-12-18 09:48:21