Major pathways of polymyxin-induced apoptosis in rat kidney proximal tubular cells
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Mohammad A K Azad1, Jesmin Akter1, Kelly L Rogers2
1Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia.
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 was 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 proportion of cells with filamentous mitochondria (regular morphology) following an 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. The mitochondrial membrane potential (Δψm) 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 have demonstrated that polymyxin-induced apoptosis is mediated through both the 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."
Insights
Polymyxin B triggers kidney cell death via both death receptor and mitochondrial pathways. Understanding these mechanisms is key to developing safer antibiotics and reducing nephrotoxicity.
Area of Science:
- Cell Biology
- Pharmacology
- Toxicology
Background:
- Polymyxins are critical antibiotics for multidrug-resistant Gram-negative infections.
- Nephrotoxicity is a significant dose-limiting side effect of polymyxin therapy.
- Identifying apoptosis pathways is essential for mitigating toxicity and developing safer alternatives.
Purpose of the Study:
- To elucidate the primary apoptotic pathways induced by polymyxin B in rat kidney proximal tubular cells (NRK-52E).
- To investigate the roles of the death receptor and mitochondrial pathways in polymyxin-induced nephrotoxicity.
Main Methods:
- Cultured rat kidney proximal tubular cells (NRK-52E) were treated with varying concentrations of polymyxin B.
- Assays were performed to measure caspase activation (caspase-3, -8, -9).
- Expression of Fas Ligand (FasL), mitochondrial morphology, mitochondrial membrane potential (Δψm), and mitochondrial superoxide production were assessed.
Main Results:
- Polymyxin B activated caspases-3, -8, and -9 in a concentration-dependent manner.
- FasL expression and mitochondrial morphology changes occurred in a concentration- and time-dependent manner.
- Polymyxin B treatment led to decreased mitochondrial membrane potential and increased mitochondrial superoxide production.
Conclusions:
- This study demonstrates that polymyxin B induces apoptosis in renal tubular cells through both death receptor and mitochondrial pathways.
- Findings provide crucial insights for ameliorating polymyxin-induced nephrotoxicity.
- The results support the development of novel, safer polymyxin-like antibiotics against Gram-negative superbugs.
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