Autophagic flux, a possible mechanism for delayed gentamicin-induced ototoxicity
| Autor: | Chunjie Tian, Yun-Hoon Choung, Oak-Sung Choo, Yeonju Kim, Beomyong Shin, You-Sun Kim, Jangho Kim |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Autophagosome Programmed cell death Time Factors Cathepsin D Pharmacology Protective Agents Membrane Fusion Models Biological Article Cell Line Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Ototoxicity Hair Cells Auditory Autophagy medicine Animals Sirolimus Cisplatin Multidisciplinary Chemistry Aminoglycoside Autophagosomes Ear medicine.disease 030104 developmental biology medicine.anatomical_structure Organ of Corti Vacuoles Gentamicins Lysosomes 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Scientific Reports(7) Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | Aminoglycoside antibiotics including gentamicin (GM) induce delayed ototoxic effects such as hearing loss after long-term use, unlike the early-onset ototoxicity caused by cisplatin. The purpose of the study was to identify the mechanism of the delayed GM-induced ototoxicity by exploring the role of autophagy in vitro and in vivo. Treating HEI-OC1 auditory cells with GM led to a time-dependent increase of the autophagosome marker LC3-II, which was accompanied by cell death. In contrast, cisplatin and penicillin caused a rapid increase and had no effect on LC3-II levels, respectively. LC3-II-expressing autophagosomes co-localized with the labeled GM. GM-treated autophagosomes expressed reduced levels of Rab7, which is necessary for the fusion of autophagosomes with lysosomes. When the autophagic flux enhancer rapamycin was applied to GM-treated cells, Rab7 and the lysosomal enzyme cathepsin D were upregulated, and increased cell survival was observed. In animal studies, the intraperitoneal injection of GM worsened hearing thresholds and induced the accumulation of LC3 in the organ of Corti. This hearing impairment was attenuated by rapamycin. These findings suggest that the delayed onset-ototoxicity of GM may be closely related to the accumulation of autophagosomes via impaired autophagy. This GM-induced auditory cell death could be inhibited by enhancing autophagic flux. |
| Databáze: | OpenAIRE |
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