PUBLICATION
Cisplatin-induced hair cell loss in zebrafish neuromasts is accompanied by protein nitration and Lmo4 degradation
- Authors
- Shahab, M., Rosati, R., Meyers, D., Sheilds, J., Crofts, E., Baker, T., Jamesdaniel, S.
- ID
- ZDB-PUB-201128-9
- Date
- 2020
- Source
- Toxicology and applied pharmacology 410: 115342 (Journal)
- Registered Authors
- Keywords
- Cisplatin, Lmo4, Neuromast, Nitrative stress, Ototoxicity
- MeSH Terms
-
- Adaptor Proteins, Signal Transducing*/metabolism
- Animals
- Animals, Genetically Modified
- Antineoplastic Agents/toxicity*
- Cisplatin/toxicity*
- Female
- Hair Cells, Auditory/drug effects*
- Hair Cells, Auditory/metabolism
- Hair Cells, Auditory/pathology
- LIM Domain Proteins*/metabolism
- Male
- Oxidative Stress/drug effects*
- Oxidative Stress/physiology
- Proteolysis/drug effects*
- Zebrafish
- PubMed
- 33245977 Full text @ Tox. App. Pharmacol.
- CTD
- 33245977
Citation
Shahab, M., Rosati, R., Meyers, D., Sheilds, J., Crofts, E., Baker, T., Jamesdaniel, S. (2020) Cisplatin-induced hair cell loss in zebrafish neuromasts is accompanied by protein nitration and Lmo4 degradation. Toxicology and applied pharmacology. 410:115342.
Abstract
Generation of reactive oxygen species, a critical factor in cisplatin-induced ototoxicity, leads to the formation of peroxynitrite, which in turn results in the nitration of susceptible proteins. Previous studies indicated that LMO4, a transcriptional regulator, is the most abundantly nitrated cochlear protein after cisplatin treatment and that LMO4 nitration facilitates ototoxicity in rodents. However, the role of this mechanism in regulating cisplatin-induced hair cell loss in non-mammalian models is unknown. As the mechanosensory hair cells in the neuromasts of zebrafish share many features with mammalian inner ear and is a good model for studying ototoxicity, we hypothesized that cisplatin treatment induces protein nitration and Lmo4 degradation in zebrafish hair cells, thereby facilitating hair cell loss. Immunostaining with anti-parvalbumin revealed a significant decrease in the number of hair cells in the neuromast of cisplatin treated larvae. In addition, cisplatin treatment induced a significant decrease in the expression of Lmo4 protein and a significant increase in nitrotyrosine levels, in the hair cells. The cisplatin-induced changes in Lmo4 and nitrotyrosine levels strongly correlated with hair cell loss, implying a potential link. Furthermore, a significant increase in the expression of activated Caspase-3 in zebrafish hair cells, post cisplatin treatment, suggested that cisplatin-induced decrease in Lmo4 levels is accompanied by apoptosis. These findings suggest that nitrative stress and Lmo4 degradation are important factors in cisplatin-induced hair cell loss in zebrafish neuromasts and that zebrafish could be used as a model to screen the otoprotective efficacy of compounds that inhibit protein nitration.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping