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Hsp70 inhibits aminoglycoside-induced hearing loss and cochlear hair cell death

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Cell Stress and Chaperones Aims and scope

Abstract

Sensory hair cells of the inner ear are sensitive to death from aging, noise trauma, and ototoxic drugs. Ototoxic drugs include the aminoglycoside antibiotics and the antineoplastic agent cisplatin. Exposure to aminoglycosides results in hair cell death that is mediated by specific apoptotic proteins, including c-Jun N-terminal kinase (JNK) and caspases. Induction of heat shock proteins (Hsps) can inhibit JNK- and caspase-dependent apoptosis in a variety of systems. We have previously shown that heat shock results in robust upregulation of Hsps in the hair cells of the adult mouse utricle in vitro. In addition, heat shock results in significant inhibition of both cisplatin- and aminoglycoside-induced hair cell death. In this system, Hsp70 is the most strongly induced Hsp, which is upregulated over 250-fold at the level of mRNA 2 h after heat shock. Hsp70 overexpression inhibits aminoglycoside-induced hair cell death in vitro. In this study, we utilized Hsp70-overexpressing mice to determine whether Hsp70 is protective in vivo. Both Hsp70-overexpressing mice and their wild-type littermates were treated with systemic kanamycin (700 mg/kg body weight) twice daily for 14 days. While kanamycin treatment resulted in significant hearing loss and hair cell death in wild-type mice, Hsp70-overexpressing mice were significantly protected against aminoglycoside-induced hearing loss and hair cell death. These data indicate that Hsp70 is protective against aminoglycoside-induced ototoxicity in vivo.

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Acknowledgments

The authors gratefully acknowledge the assistance of Dr. Hainan Lang and Dr. Richard Schmiedt in the initial setup and calibrations for the ABR recordings. This work was supported by NIH 5 R01 DC 007613, NIH/NCRR extramural research facilities construction (C06) grants C06 RR015455, and C06 RR14516 from the Extramural Research Facilities Program of the National Center for Research Resources.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Medical University of South Carolina, 171 Ashley Avenue, MSC 908, Charleston, SC, 29425, USA

    Mona Taleb, Carlene S. Brandon & Lisa L. Cunningham

  2. Department of Otolaryngology–Head and Neck Surgery, Medical University of South Carolina, Charleston, SC, 29425, USA

    Fu-Shing Lee & Kelly C. Harris

  3. Department of Endocrinology, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA

    Wolfgang H. Dillmann

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  1. Mona Taleb
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  2. Carlene S. Brandon
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  3. Fu-Shing Lee
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  4. Kelly C. Harris
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  5. Wolfgang H. Dillmann
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  6. Lisa L. Cunningham
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Correspondence to Lisa L. Cunningham.

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Taleb, M., Brandon, C.S., Lee, FS. et al. Hsp70 inhibits aminoglycoside-induced hearing loss and cochlear hair cell death. Cell Stress and Chaperones 14, 427–437 (2009). https://doi.org/10.1007/s12192-008-0097-2

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