Polymyxin B Induces Apoptosis in Kidney Proximal Tubular Cells

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bIdentifying 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 concentrationdependent 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 (⌬ m ) 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."

Section: Discussionmentioning

confidence: 99%

Major Pathways of Polymyxin-Induced Apoptosis in Rat Kidney Proximal Tubular Cells

Azad

Akter

Rogers

et al. 2015

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“…Clearly, the implications of such dosage regimens on nephrotoxicity should be carefully considered. The key drivers of polymyxin-induced nephrotoxicity are the subject of continuing research (46)(47)(48)(49), and findings from those studies will be integral to the development of clinical guidelines for safe and effective polymyxin B dosing.…”

Section: Discussionmentioning

confidence: 99%

“…The volume and temperature of the central reservoir were 80 ml and 37°C, respectively, and cation-adjusted Mueller-Hinton broth was circulated at a rate of 4.8 ml/h to achieve an elimination half-life of 11.6 h. Viable counting was performed on drug-free and drug-containing (6.6 mg/liter polymyxin B base) plates at 0, 0.5, 1, 2, 4, 8,11,13,23,25,26,28,47,49,50,52,71,73,74,76, and 96 h. The PAPs were performed at 0, 23, 47, 71, and 96 h on polymyxin B-containing plates (1.7, 3.3, and 6.6 mg/liter polymyxin B base). Polymyxin B and colistin concentrations were measured using a previously described and validated liquid chromatography-tandem mass spectrometry assay (29).…”

Section: Methodsmentioning

confidence: 99%

Colistin and Polymyxin B Dosage Regimens against Acinetobacter baumannii: Differences in Activity and the Emergence of Resistance

Cheah

Tsuji

et al. 2016

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dInfections caused by multidrug-resistant Acinetobacter baumannii are a major public health problem, and polymyxins are often the last line of therapy for recalcitrant infections by such isolates. The pharmacokinetics of the two clinically used polymyxins, polymyxin B and colistin, differ considerably, since colistin is administered as an inactive prodrug that undergoes slow conversion to colistin. However, the impact of these substantial pharmacokinetic differences on bacterial killing and resistance emergence is poorly understood. We assessed clinically relevant polymyxin B and colistin dosage regimens against one reference and three clinical A. baumannii strains in a dynamic one-compartment in vitro model. A new mechanism-based pharmacodynamic model was developed to describe and predict the drug concentrations and viable counts of the total and resistant populations. Rapid attainment of target concentrations was shown to be critical for polymyxin-induced bacterial killing. All polymyxin B regimens achieved peak concentrations of at least 1 mg/liter within 1 h and caused >4 log 10 killing at 1 h. In contrast, the slow rise of colistin concentrations to 3 mg/liter over 48 h resulted in markedly reduced bacterial killing. A significant (4 to 6 log 10 CFU/ ml) amplification of resistant bacterial populations was common to all dosage regimens. The developed mechanism-based model explained the observed bacterial killing, regrowth, and resistance. The model also implicated adaptive polymyxin resistance as a key driver of bacterial regrowth and predicted the amplification of preexisting, highly polymyxin-resistant bacterial populations following polymyxin treatment. Antibiotic combination therapies seem the most promising option for minimizing the emergence of polymyxin resistance.

“…For both colistin and polymyxin B, only a very minor proportion of the dose is renally eliminated (8,10); the majority appears to undergo extensive reabsorption after being filtered by glomeruli (8), leading to accumulation in renal tubular cells and subsequently to apoptosis and tubular damage (6,7,(10)(11)(12). Recent studies from our laboratory have demonstrated that polymyxin-induced apoptosis in renal tubular cells appears to be mediated by oxidative stress (11,13). Reactive oxygen species (ROS) molecules are mainly generated by mitochondria and are among the major mediators of oxidative stress; they initiate renal cell apoptosis, which finally leads to renal dysfunction (14,15).…”

mentioning

confidence: 99%

Lycopene Attenuates Colistin-Induced Nephrotoxicity in Mice via Activation of the Nrf2/HO-1 Pathway

Dai

Tang

Deng

et al. 2015

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103

bNephrotoxicity is the major dose-limiting factor for the clinical use of colistin against multidrug-resistant (MDR) Gram-negative bacteria. This study aimed to investigate the protective effect of lycopene on colistin-induced nephrotoxicity in a mouse model. Fifty mice were randomly divided into 5 groups: the control group (saline solution), the lycopene group (20 mg/kg of body weight/day administered orally), the colistin group (15 mg/kg/day administered intravenously), the colistin (15 mg/kg/day) plus lycopene (5 mg/kg/day) group, and the colistin (15 mg/kg/day) plus lycopene (20 mg/kg/day) group; all mice were treated for 7 days. At 12 h after the last dose, blood was collected for measurements of blood urea nitrogen (BUN) and serum creatinine levels. The kidney tissue samples were obtained for examination of biomarkers of oxidative stress and apoptosis, histopathological assessment, and quantitative reverse transcription-PCR (qRT-PCR) analysis. Colistin treatment significantly increased concentrations of BUN and serum creatinine, tubular apoptosis/necrosis, lipid peroxidation, and heme oxygenase 1 (HO-1) activity, while the treatment decreased the levels of endogenous antioxidant biomarkers glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD). Notably, the changes in the levels of all biomarkers were attenuated in the kidneys of mice treated with colistin by lycopene (5 or 20 mg/kg). Lycopene treatment, especially in the colistin plus lycopene (20 mg/kg) group, significantly downregulated the expression of NF-B mRNA (P < 0.01) but upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and HO-1 mRNA (both P < 0.01) in the kidney compared with the results seen with the colistin group. Our data demonstrated that coadministration of 20 mg/kg/day lycopene can protect against colistin-induced nephrotoxicity in mice. This effect may be attributed to the antioxidative property of lycopene and its ability to activate the Nrf2/HO-1 pathway.