Abstract
The ototoxic side effect of cisplatin is a main cause of sensorineural hearing loss. This side effect limits the clinical application of cisplatin and affects patients’ quality of life. This study was designed to investigate the effect of apelin-13 on cisplatin-induced C57BL/6 mice hearing loss model and explore the potential underlying molecular mechanisms. Mice were intraperitoneally injected with 100 μg/kg apelin-13 2 h before 3 mg/kg cisplatin injection for 7 consecutive days. Cochlear explants cultured in vitro were pretreated with 10 nM apelin-13 2 h prior to 30 μM cisplatin treatment for another 24 h. Hearing test and morphology results showed that apelin-13 attenuated cisplatin-induced mice hearing loss and protected cochlear hair cells and spiral ganglion neurons from damage. In vivo and in vitro experimental results showed that apelin-3 reduced cisplatin-induced apoptosis of hair cells and spiral ganglion neurons. In addition, apelin-3 preserved mitochondrial membrane potential and inhibited ROS production in cultured cochlear explants. Mechanistic studies showed that apelin-3 decreased cisplatin-induced cleaved caspase 3 expression but increased Bcl-2; inhibited the expression of pro-inflammatory factors TNF-a and IL-6; and increased STAT1 phosphorylation but decreased STAT3 phosphorylation. In conclusion, our results indicate that apelin-13 could be a potential otoprotective agent to prevent cisplatin-induced ototoxicity by inhibiting apoptosis, ROS production, TNF-α and IL-6 expression, and regulating phosphorylation of STAT1 and STAT3 transcription factors.
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The datasets generated during and/or analyzed during the current study are available from the corresponding author on request.
Abbreviations
- STAT1:
-
Signal transducer and activator of transcription 1
- STAT3:
-
Signal transducer and activator of transcription 3
- HCs:
-
Hair cells
- SGNs:
-
Spiral ganglion neurons
- ABR:
-
Auditory brainstem response
- HE:
-
Hematoxylin and eosin staining
- TUNEL:
-
TdT-mediated dUTP nick-end labeling
- ROS:
-
Reactive oxygen species
- TNF-α:
-
Tumor necrosis factor α
- IL-6:
-
Interleukin-6
- P-STAT1:
-
Phosphorylated signal transducer and activator of transcription 1
- P-STAT3:
-
Phosphorylated signal transducer and activator of transcription 3
- ELISA:
-
Enzyme-linked immunosorbent assay
- MAPK/Akt:
-
Mitogen-activated protein kinase/ protein kinase B
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Funding
This work was supported by the National Natural Science Foundation of China [Grant number 82000979, 82101215]; the Fund of Lin He Academician Workstation of Jining Medical University [Grant number JYHL2019MS13]; National College Students' innovation and entrepreneurship training program [Grant number 202110443040]; the Natural Science Foundation of Jiangsu Province [grant number BK20200201].
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HY: experimental design, methodology, writing—original draft. QY: writing—reviewing and editing. YS and BY: conducted experimental procedures, data collecting and analyzing. HZ and FW: software, investigation. YG, LZ, and WZ: conceptualization, data analyzing, validation.
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This study was approved by the Medical Ethics Committee of Jining Medical University (2019-JC-001).
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Yin, H., Sun, Y., Ya, B. et al. Apelin-13 protects against cisplatin-induced ototoxicity by inhibiting apoptosis and regulating STAT1 and STAT3. Arch Toxicol 97, 2477–2493 (2023). https://doi.org/10.1007/s00204-023-03544-x
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DOI: https://doi.org/10.1007/s00204-023-03544-x