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Cisplatin-Induced Ototoxicity in Rats Is Driven by RIP3-Dependent Necroptosis

Cisplatin-induced early-onset ototoxicity is linked to hearing loss. The mechanism by which cisplatin causes ototoxicity remains unclear. The purpose of this study was to identify the involvement of receptor-interacting protein kinase (RIP)3-dependent necroptosis in cisplatin-induced ototoxicity in...

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Autores principales: Choi, Mi-Jin, Kang, Hyunsook, Lee, Yun Yeong, Choo, Oak-Sung, Jang, Jeong Hun, Park, Sung-Hee, Moon, Jong-Seok, Choi, Seong Jun, Choung, Yun-Hoon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562419/
https://www.ncbi.nlm.nih.gov/pubmed/31052605
http://dx.doi.org/10.3390/cells8050409
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author Choi, Mi-Jin
Kang, Hyunsook
Lee, Yun Yeong
Choo, Oak-Sung
Jang, Jeong Hun
Park, Sung-Hee
Moon, Jong-Seok
Choi, Seong Jun
Choung, Yun-Hoon
author_facet Choi, Mi-Jin
Kang, Hyunsook
Lee, Yun Yeong
Choo, Oak-Sung
Jang, Jeong Hun
Park, Sung-Hee
Moon, Jong-Seok
Choi, Seong Jun
Choung, Yun-Hoon
author_sort Choi, Mi-Jin
collection PubMed
description Cisplatin-induced early-onset ototoxicity is linked to hearing loss. The mechanism by which cisplatin causes ototoxicity remains unclear. The purpose of this study was to identify the involvement of receptor-interacting protein kinase (RIP)3-dependent necroptosis in cisplatin-induced ototoxicity in vitro and in vivo. Sprague–Dawley rats (SD, 8 week) were treated via intraperitoneal (i.p.) injection with cisplatin (16 mg/kg for 1 day), and their hearing thresholds were measured by the auditory brainstem response (ABR) method. Hematoxylin and eosin (H & E) staining, immunohistochemistry, and western blots were performed to determine the effect of cisplatin-induced ototoxicity on cochlear morphology. Inhibitor experiments with necrostatin 1 (Nec-1) and Z-VAD were also performed in HEI-OC1 cell line. H&E stains revealed that the necroptotic changes were increased in the organ of Corti (OC) and spiral ganglion neurons (SGNs). Moreover, immunohistochemistry and western blot analysis showed that cisplatin treatment increased the protein levels of RIP3 in both OCs and SGNs. The treatment of Nec-1, a selective RIP1 inhibitor, resulted in markedly suppression of cisplatin-induced cell death in HEI-OC1 cells, whereas Z-VAD treatment did not change the cisplatin-induced cell death. Our results suggest that RIP3-dependent necroptosis was substantial in cisplatin-induced ototoxicity; inner cochlear regions, the OCs, and SGNs were especially sensitive to necroptosis.
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spelling pubmed-65624192019-06-17 Cisplatin-Induced Ototoxicity in Rats Is Driven by RIP3-Dependent Necroptosis Choi, Mi-Jin Kang, Hyunsook Lee, Yun Yeong Choo, Oak-Sung Jang, Jeong Hun Park, Sung-Hee Moon, Jong-Seok Choi, Seong Jun Choung, Yun-Hoon Cells Article Cisplatin-induced early-onset ototoxicity is linked to hearing loss. The mechanism by which cisplatin causes ototoxicity remains unclear. The purpose of this study was to identify the involvement of receptor-interacting protein kinase (RIP)3-dependent necroptosis in cisplatin-induced ototoxicity in vitro and in vivo. Sprague–Dawley rats (SD, 8 week) were treated via intraperitoneal (i.p.) injection with cisplatin (16 mg/kg for 1 day), and their hearing thresholds were measured by the auditory brainstem response (ABR) method. Hematoxylin and eosin (H & E) staining, immunohistochemistry, and western blots were performed to determine the effect of cisplatin-induced ototoxicity on cochlear morphology. Inhibitor experiments with necrostatin 1 (Nec-1) and Z-VAD were also performed in HEI-OC1 cell line. H&E stains revealed that the necroptotic changes were increased in the organ of Corti (OC) and spiral ganglion neurons (SGNs). Moreover, immunohistochemistry and western blot analysis showed that cisplatin treatment increased the protein levels of RIP3 in both OCs and SGNs. The treatment of Nec-1, a selective RIP1 inhibitor, resulted in markedly suppression of cisplatin-induced cell death in HEI-OC1 cells, whereas Z-VAD treatment did not change the cisplatin-induced cell death. Our results suggest that RIP3-dependent necroptosis was substantial in cisplatin-induced ototoxicity; inner cochlear regions, the OCs, and SGNs were especially sensitive to necroptosis. MDPI 2019-05-02 /pmc/articles/PMC6562419/ /pubmed/31052605 http://dx.doi.org/10.3390/cells8050409 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Choi, Mi-Jin
Kang, Hyunsook
Lee, Yun Yeong
Choo, Oak-Sung
Jang, Jeong Hun
Park, Sung-Hee
Moon, Jong-Seok
Choi, Seong Jun
Choung, Yun-Hoon
Cisplatin-Induced Ototoxicity in Rats Is Driven by RIP3-Dependent Necroptosis
title Cisplatin-Induced Ototoxicity in Rats Is Driven by RIP3-Dependent Necroptosis
title_full Cisplatin-Induced Ototoxicity in Rats Is Driven by RIP3-Dependent Necroptosis
title_fullStr Cisplatin-Induced Ototoxicity in Rats Is Driven by RIP3-Dependent Necroptosis
title_full_unstemmed Cisplatin-Induced Ototoxicity in Rats Is Driven by RIP3-Dependent Necroptosis
title_short Cisplatin-Induced Ototoxicity in Rats Is Driven by RIP3-Dependent Necroptosis
title_sort cisplatin-induced ototoxicity in rats is driven by rip3-dependent necroptosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562419/
https://www.ncbi.nlm.nih.gov/pubmed/31052605
http://dx.doi.org/10.3390/cells8050409
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