Polymyxin B Nephrotoxicity: From Organ to Cell Damage

Polymyxin B Nephrotoxicity: From Organ to Cell Damage

Author Fernandes Vattimo, Maria de Fatima Google Scholar
Watanabe, Mirian Google Scholar
da Fonseca, Cassiane Dezoti Google Scholar
de Moura Neiva, Luciana Barros Google Scholar
Pessoa, Edson Andrade Autor UNIFESP Google Scholar
Borges, Fernanda Teixeira Autor UNIFESP Google Scholar
Abstract 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 mu M, 75 mu M and 375 mu M 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.
Language English
Sponsor Fundacao de Amparo a Pesquisa do Estado de Sao Paulo
[2013/26560-2]
[2011/24028-6]
Grant number FAPESP:2013/26560-2
2011/24028-6
Date 2016
Published in Plos One. San Francisco, v. 11, n. 8, p. -, 2016.
ISSN 1932-6203 (Sherpa/Romeo, impact factor)
Publisher Public Library Science
Extent -
Origin http://dx.doi.org/10.1371/journal.pone.0161057
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000381487600057
URI http://repositorio.unifesp.br/handle/11600/51167

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