Vancomycin induces reactive oxygen species-dependent apoptosis via mitochondrial cardiolipin peroxidation in renal tubular epithelial cells

Yuya Sakamoto, Takahisa Yano, Yuki Hanada, Aki Takeshita, Fumika Inagaki, Satohiro Masuda, Naoya Matsunaga, Satoru Koyanagi, Shigehiro Ohdo

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Abstract

Vancomycin (VCM) is a first-line antibiotic for serious infections caused by methicillin-resistant Staphylococcus aureus. However, nephrotoxicity is one of the most complaint in VCM therapy. We previously reported that VCM induced apoptosis in a porcine proximal tubular epithelial cell line (LLC-PK1), in which mitochondrial complex I may generate superoxide, leading to cell death. In the present study, VCM caused production of mitochondrial reactive oxygen species and peroxidation of the mitochondrial phospholipid cardiolipin that was reversed by administration of the mitochondrial uncoupler carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP). FCCP also significantly suppressed VCM-induced depolarization of the mitochondrial membrane and apoptosis. Moreover, the lipophilic antioxidant vitamin E and a mitochondria-targeted antioxidant, mitoTEMPO, also significantly suppressed VCM-induced depolarization of mitochondrial membrane and apoptosis, whereas vitamin C, n-acetyl cysteine, or glutathione did not provide significant protection. These findings suggest that peroxidation of the mitochondrial membrane cardiolipin mediated the VCM-induced production of intracellular reactive oxygen species and initiation of apoptosis in LLC-PK1 cells. Furthermore, regulation of mitochondrial function using a mitochondria-targeted antioxidant, such as mitoTEMPO, may constitute a potential strategy for mitigation of VCM-induced proximal tubular epithelial cell injury.

Original languageEnglish
Pages (from-to)48-56
Number of pages9
JournalEuropean Journal of Pharmacology
Volume800
DOIs
Publication statusPublished - Jan 1 2017

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Cardiolipins
Vancomycin
Reactive Oxygen Species
Epithelial Cells
Apoptosis
Kidney
Mitochondrial Membranes
Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone
Antioxidants
Mitochondria
LLC-PK1 Cells
Methicillin-Resistant Staphylococcus aureus
Vitamin E
Superoxides
Ascorbic Acid
Glutathione
Cysteine
Phospholipids
Cell Death
Swine

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Vancomycin induces reactive oxygen species-dependent apoptosis via mitochondrial cardiolipin peroxidation in renal tubular epithelial cells. / Sakamoto, Yuya; Yano, Takahisa; Hanada, Yuki; Takeshita, Aki; Inagaki, Fumika; Masuda, Satohiro; Matsunaga, Naoya; Koyanagi, Satoru; Ohdo, Shigehiro.

In: European Journal of Pharmacology, Vol. 800, 01.01.2017, p. 48-56.

Research output: Contribution to journalArticle

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