Ethambutol induces impaired autophagic flux and apoptosis in the rat retina

Ethambutol (EMB), an effective first-line antituberculosis agent, can cause serious visual impairment or irreversible vision loss in a significant number of patients. However, the mechanism underlying this ocular cytotoxicity remains to be elucidated. In this study, we found that there were statisti...

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Main Authors:	Huang, Shun-Ping, Chien, Jia-Ying, Tsai, Rong-Kung
Format:	Online
Language:	English
Published:	The Company of Biologists 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4527287/

id	pubmed-4527287
recordtype	oai_dc
spelling	pubmed-45272872015-09-03 Ethambutol induces impaired autophagic flux and apoptosis in the rat retina Huang, Shun-Ping Chien, Jia-Ying Tsai, Rong-Kung Research Article Ethambutol (EMB), an effective first-line antituberculosis agent, can cause serious visual impairment or irreversible vision loss in a significant number of patients. However, the mechanism underlying this ocular cytotoxicity remains to be elucidated. In this study, we found that there were statistically significant dose- and time-dependent increases in the number of cytoplasmic vacuoles and the level of cell death in EMB-treated RGC-5 cells (retinal ganglion cells). The protein kinase C (PKC)δ inhibitor rottlerin markedly reduced the EMB-induced activation of caspase-3 and the subsequent apoptosis of RGC-5 cells. Western blot analysis revealed that the expression levels of class III PI3K, Beclin-1, p62 and LC3-II were upregulated, and LC3 immunostaining results showed activation of the early phase and inhibition of the late stage of autophagy in retinas of the EMB-intraperitoneal (IP)-injected rat model. We further demonstrated that exposure to EMB induces autophagosome accumulation, which results from the impaired autophagic flux that is mediated by a PKCδ-dependent pathway, inhibits the PI3K/Akt/mTOR signaling pathway and leads to apoptotic death in retina neuronal cells. These results indicate that autophagy dysregulation in retinal neuronal cells might play a substantial role in EMB-induced optic neuroretinopathy. The Company of Biologists 2015-08-01 /pmc/articles/PMC4527287/ /pubmed/26092127 http://dx.doi.org/10.1242/dmm.019737 Text en © 2015. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Huang, Shun-Ping Chien, Jia-Ying Tsai, Rong-Kung
spellingShingle	Huang, Shun-Ping Chien, Jia-Ying Tsai, Rong-Kung Ethambutol induces impaired autophagic flux and apoptosis in the rat retina
author_facet	Huang, Shun-Ping Chien, Jia-Ying Tsai, Rong-Kung
author_sort	Huang, Shun-Ping
title	Ethambutol induces impaired autophagic flux and apoptosis in the rat retina
title_short	Ethambutol induces impaired autophagic flux and apoptosis in the rat retina
title_full	Ethambutol induces impaired autophagic flux and apoptosis in the rat retina
title_fullStr	Ethambutol induces impaired autophagic flux and apoptosis in the rat retina
title_full_unstemmed	Ethambutol induces impaired autophagic flux and apoptosis in the rat retina
title_sort	ethambutol induces impaired autophagic flux and apoptosis in the rat retina
description	Ethambutol (EMB), an effective first-line antituberculosis agent, can cause serious visual impairment or irreversible vision loss in a significant number of patients. However, the mechanism underlying this ocular cytotoxicity remains to be elucidated. In this study, we found that there were statistically significant dose- and time-dependent increases in the number of cytoplasmic vacuoles and the level of cell death in EMB-treated RGC-5 cells (retinal ganglion cells). The protein kinase C (PKC)δ inhibitor rottlerin markedly reduced the EMB-induced activation of caspase-3 and the subsequent apoptosis of RGC-5 cells. Western blot analysis revealed that the expression levels of class III PI3K, Beclin-1, p62 and LC3-II were upregulated, and LC3 immunostaining results showed activation of the early phase and inhibition of the late stage of autophagy in retinas of the EMB-intraperitoneal (IP)-injected rat model. We further demonstrated that exposure to EMB induces autophagosome accumulation, which results from the impaired autophagic flux that is mediated by a PKCδ-dependent pathway, inhibits the PI3K/Akt/mTOR signaling pathway and leads to apoptotic death in retina neuronal cells. These results indicate that autophagy dysregulation in retinal neuronal cells might play a substantial role in EMB-induced optic neuroretinopathy.
publisher	The Company of Biologists
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4527287/
_version_	1613256553033367552

Ethambutol induces impaired autophagic flux and apoptosis in the rat retina

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