Polymyxin B Nephrotoxicity: From Organ to Cell Damage

Polymyxins have a long history of dose-limiting toxicity, but the underlying mechanism of polymyxin B-induced nephrotoxicity is unclear. This study investigated the link between the nephrotoxic effects of polymyxin B on renal metabolic functions and mitochondrial morphology in rats and on the struct...

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Published in:PloS one 2016-08, Vol.11 (8), p.e0161057
Main Authors: Vattimo, Maria de Fátima Fernandes, Watanabe, Mirian, da Fonseca, Cassiane Dezoti, Neiva, Luciana Barros de Moura, Pessoa, Edson Andrade, Borges, Fernanda Teixeira
Format: Article
Language:English
Subjects:
Animals
Anti-Bacterial Agents - pharmacokinetics
Anti-Bacterial Agents - toxicity
Apoptosis
Apoptosis - drug effects
Biology and Life Sciences
Cell Survival - drug effects
Clinical medicine
Complications and side effects
Creatinine
Cytochrome
Cytochrome c
Cytochromes c - metabolism
Cytotoxicity
Damage assessment
Damage localization
Dehydrogenase
Dosage and administration
Drug dosages
Electron microscopy
Hemodynamics
Ischemia
Kidney - drug effects
Kidney - metabolism
Kidney - pathology
Kidneys
L-Lactate dehydrogenase
L-Lactate Dehydrogenase - metabolism
Laboratory animals
Lactate dehydrogenase
Lactic acid
LLC-PK1 Cells
Localization
Lymphocytes B
Male
Medicine and Health Sciences
Metabolism
Microscopy, Electron, Transmission
Mitochondria
Mitochondria - drug effects
Mitochondria - metabolism
Mitochondria - pathology
Mitochondrial diseases
Necrosis
Nephrology
Nitric oxide
Nitric Oxide - metabolism
Nursing schools
Oxidation resistance
Oxidative stress
Oxidative Stress - drug effects
Polymyxin B
Polymyxin B - pharmacokinetics
Polymyxin B - toxicity
Polymyxins
Position (location)
Rats
Rats, Wistar
Renal cortex
Renal function
Research and Analysis Methods
Rhodamine
Risk factors
Rodents
Side effects
Sodium chloride
Structural integrity
Swine
Toxicity
Urine
Veins & arteries
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Summary:Polymyxins have a long history of dose-limiting toxicity, but the underlying mechanism of polymyxin B-induced nephrotoxicity is unclear. This study investigated the link between the nephrotoxic effects of polymyxin B on renal metabolic functions and mitochondrial morphology in rats and on the structural integrity of LLC-PK1 cells. Fifteen Wistar rats were divided into two groups: Saline group, rats received 3 mL/kg of 0.9% NaCl intraperitoneally (i.p.) once a day for 5 days; Polymyxin B group, rats received 4 mg/kg/day of polymyxin B i.p. once a day for 5 days. Renal function, renal hemodynamics, oxidative stress, mitochondrial injury and histological characteristics were assessed. Cell membrane damage was evaluated via lactate dehydrogenase and nitric oxide levels, cell viability, and apoptosis in cells exposed to 12.5 μM, 75 μM and 375 μM polymyxin B. Polymyxin B was immunolocated using Lissamine rhodamine-polymyxin B in LLC-PK1 cells. Polymyxin B administration in rats reduced creatinine clearance and increased renal vascular resistance and oxidative damage. Mitochondrial damage was confirmed by electron microscopy and cytosolic localization of cytochrome c. Histological analysis revealed tubular dilatation and necrosis in the renal cortex. The reduction in cell viability and the increase in apoptosis, lactate dehydrogenase levels and nitric oxide levels confirmed the cytotoxicity of polymyxin B. The incubation of LLC-PK1 cells resulted in mitochondrial localization of polymyxin B. This study demonstrates that polymyxin B nephrotoxicity is characterized by mitochondrial dysfunction and free radical generation in both LLC-PK1 cells and rat kidneys. These data also provide support for clinical studies on the side effects of polymyxin B.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0161057