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

Abstract

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."

Methionine Ameliorates Polymyxin-Induced Nephrotoxicity by Attenuating Cellular Oxidative Stress

“…The majority of the filtered polymyxin molecules undergo extensive tubular reabsorption, leading to the very significant accumulation of polymyxin in tubular cells, which causes renal tubular damage (9,(11)(12)(13). Our recent studies demonstrated that polymyxin-induced nephrotoxicity involves apoptosis in kidney tubular cells, which appears to be partially mediated by the generation of reactive oxygen species (ROS) and caspase activation (14)(15)(16). It has been demonstrated that several antioxidants can attenuate polymyxin-induced nephrotoxicity in animals (16)(17)(18)(19).…”

Changes in expression of genes related to caspases and BCL-2 family in RPTEC treated with amphotericin B and its modified forms

“…Both, caspase-related and BCL-2 proteins, due to participation in the regulation of apoptosis, may be involved in processes related to drug toxicity. It has been found, among others, that caspases are activated during renal cell injury in response to antibiotics [8,9]. One of most important drugs used for systemic fungal infection treatment is amphotericin B (AmB)a natural macrolide antibiotic produced mainly by actinomycetes of the genus Streptomyces.…”

Genetic Variants Contributing to Colistin Cytotoxicity: Identification of TGIF1 and HOXD10 Using a Population Genomics Approach

“…In clinical settings, the drug is administered as an anionic prodrug, colistin methanosulfate, which is subsequently hydrolyzed to the cationic colistin [3]. The major toxicities of colistin include nephrotoxicity [4] and neurotoxicity [5]. The use of colistin is often limited by nephrotoxicity, affecting up to 55% of recipients [6,7,8,9,10].…”