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A protective mechanism against antibiotic-induced ototoxicity: role of prestin.

Yu L, Jiang XH, Zhou Z, Tsang LL, Yu MK, Chung YW, Zhang XH, Wang AM, Tang H, Chan HC - PLoS ONE (2011)

Bottom Line: Hearing loss or ototoxicity is one of the major side effects associated with the use of the antibiotics, particularly aminoglycosides (AGs), which are the most commonly used antibiotics worldwide.In the present study, we test the possibility that prestin, the motor protein specifically expressed in the basolateral membrane of outer hair cells (OHCs) in the cochlea with electromotility responsible for sound amplification, may be involved in the process of AG-induced apoptosis in OHCs.Our results from both mice model and cultured cell line indicate a previously unexpected role of prestin, in mediating antibiotic-induced apoptosis, the effect of which is associated with its anion-transporting capacity.

View Article: PubMed Central - PubMed

Affiliation: Epithelial Cells Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, ShaTin, Hong Kong.

ABSTRACT
Hearing loss or ototoxicity is one of the major side effects associated with the use of the antibiotics, particularly aminoglycosides (AGs), which are the most commonly used antibiotics worldwide. However, the molecular and cellular events involved in the antibiotic-induced ototoxicity remains unclear. In the present study, we test the possibility that prestin, the motor protein specifically expressed in the basolateral membrane of outer hair cells (OHCs) in the cochlea with electromotility responsible for sound amplification, may be involved in the process of AG-induced apoptosis in OHCs. Our results from both mice model and cultured cell line indicate a previously unexpected role of prestin, in mediating antibiotic-induced apoptosis, the effect of which is associated with its anion-transporting capacity. The observed downregulation of prestin mRNA prior to detectable apoptosis in OHCs and hearing loss in the antibiotic-treated mice is interesting, which may serve as a protective mechanism against hearing loss induced by AGs in the early stage.

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Prestin-enhanced kanamycin-induced apoptosis depends on extracellular chloride.Control or prestin-transfected CHO cells were exposed to 100 µM kanamycin for 2 h in the presence or absence of extracellular chloride in KH media. Normal culture media F-12K was used as a control. (A): TUNEL staining showed when cells were incubated in chloride-free KH solution, the kanamycin-induced effect in prestin-expressing CHO cells was abolished. *,p<0.05. (B): Western blot analysis of bcl-2 expression in control and prestin-transfected cells upon 100 µM kanamycin treatment in KH media with or without chloride for 2 h. *,p<0.05. Images are representative of 3 separate experiments.
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pone-0017322-g005: Prestin-enhanced kanamycin-induced apoptosis depends on extracellular chloride.Control or prestin-transfected CHO cells were exposed to 100 µM kanamycin for 2 h in the presence or absence of extracellular chloride in KH media. Normal culture media F-12K was used as a control. (A): TUNEL staining showed when cells were incubated in chloride-free KH solution, the kanamycin-induced effect in prestin-expressing CHO cells was abolished. *,p<0.05. (B): Western blot analysis of bcl-2 expression in control and prestin-transfected cells upon 100 µM kanamycin treatment in KH media with or without chloride for 2 h. *,p<0.05. Images are representative of 3 separate experiments.

Mentions: Since anion fluxes have been implicated in regulating apoptotic activities in different cell types [23], [24], the requirement of prestin in mediating the kanamycin-induced chloride influx suggests that the anion-transporting property induced by prestin is likely to contribute to the kanamycin-induced apoptosis. In other words, the kanamycin-induced apoptosis should depend on both prestin and extracellular chloride. To test this, we treated either the control or prestin-transfected CHO cells with kanamycin in the presence or absence of extracellular chloride in Krebs-Henseleit (KH) solution, the ion composition of which could be manually manipulated. As shown in Fig. 5, forced expression of prestin significantly potentiated kanamycin-induced apoptosis as detected by TUNEL assay compared with the prestin-lacking control when cells were incubated in the chloride-containing KH solution, which was similar to that when cells were incubated in chloride-containing culture media (Fig. 5A). When cells were incubated in chloride-free KH solution, the kanamycin-induced effect in prestin-expressing CHO cells was abolished, indicating that the kanamycin-induced apoptosis depended on extracellular chloride. Thus, it appears that the anion-transporting capacity induced by prestin is involved in mediating the enhancement effect of prestin on the kanamycin-induced apoptosis.


A protective mechanism against antibiotic-induced ototoxicity: role of prestin.

Yu L, Jiang XH, Zhou Z, Tsang LL, Yu MK, Chung YW, Zhang XH, Wang AM, Tang H, Chan HC - PLoS ONE (2011)

Prestin-enhanced kanamycin-induced apoptosis depends on extracellular chloride.Control or prestin-transfected CHO cells were exposed to 100 µM kanamycin for 2 h in the presence or absence of extracellular chloride in KH media. Normal culture media F-12K was used as a control. (A): TUNEL staining showed when cells were incubated in chloride-free KH solution, the kanamycin-induced effect in prestin-expressing CHO cells was abolished. *,p<0.05. (B): Western blot analysis of bcl-2 expression in control and prestin-transfected cells upon 100 µM kanamycin treatment in KH media with or without chloride for 2 h. *,p<0.05. Images are representative of 3 separate experiments.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3045444&req=5

pone-0017322-g005: Prestin-enhanced kanamycin-induced apoptosis depends on extracellular chloride.Control or prestin-transfected CHO cells were exposed to 100 µM kanamycin for 2 h in the presence or absence of extracellular chloride in KH media. Normal culture media F-12K was used as a control. (A): TUNEL staining showed when cells were incubated in chloride-free KH solution, the kanamycin-induced effect in prestin-expressing CHO cells was abolished. *,p<0.05. (B): Western blot analysis of bcl-2 expression in control and prestin-transfected cells upon 100 µM kanamycin treatment in KH media with or without chloride for 2 h. *,p<0.05. Images are representative of 3 separate experiments.
Mentions: Since anion fluxes have been implicated in regulating apoptotic activities in different cell types [23], [24], the requirement of prestin in mediating the kanamycin-induced chloride influx suggests that the anion-transporting property induced by prestin is likely to contribute to the kanamycin-induced apoptosis. In other words, the kanamycin-induced apoptosis should depend on both prestin and extracellular chloride. To test this, we treated either the control or prestin-transfected CHO cells with kanamycin in the presence or absence of extracellular chloride in Krebs-Henseleit (KH) solution, the ion composition of which could be manually manipulated. As shown in Fig. 5, forced expression of prestin significantly potentiated kanamycin-induced apoptosis as detected by TUNEL assay compared with the prestin-lacking control when cells were incubated in the chloride-containing KH solution, which was similar to that when cells were incubated in chloride-containing culture media (Fig. 5A). When cells were incubated in chloride-free KH solution, the kanamycin-induced effect in prestin-expressing CHO cells was abolished, indicating that the kanamycin-induced apoptosis depended on extracellular chloride. Thus, it appears that the anion-transporting capacity induced by prestin is involved in mediating the enhancement effect of prestin on the kanamycin-induced apoptosis.

Bottom Line: Hearing loss or ototoxicity is one of the major side effects associated with the use of the antibiotics, particularly aminoglycosides (AGs), which are the most commonly used antibiotics worldwide.In the present study, we test the possibility that prestin, the motor protein specifically expressed in the basolateral membrane of outer hair cells (OHCs) in the cochlea with electromotility responsible for sound amplification, may be involved in the process of AG-induced apoptosis in OHCs.Our results from both mice model and cultured cell line indicate a previously unexpected role of prestin, in mediating antibiotic-induced apoptosis, the effect of which is associated with its anion-transporting capacity.

View Article: PubMed Central - PubMed

Affiliation: Epithelial Cells Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, ShaTin, Hong Kong.

ABSTRACT
Hearing loss or ototoxicity is one of the major side effects associated with the use of the antibiotics, particularly aminoglycosides (AGs), which are the most commonly used antibiotics worldwide. However, the molecular and cellular events involved in the antibiotic-induced ototoxicity remains unclear. In the present study, we test the possibility that prestin, the motor protein specifically expressed in the basolateral membrane of outer hair cells (OHCs) in the cochlea with electromotility responsible for sound amplification, may be involved in the process of AG-induced apoptosis in OHCs. Our results from both mice model and cultured cell line indicate a previously unexpected role of prestin, in mediating antibiotic-induced apoptosis, the effect of which is associated with its anion-transporting capacity. The observed downregulation of prestin mRNA prior to detectable apoptosis in OHCs and hearing loss in the antibiotic-treated mice is interesting, which may serve as a protective mechanism against hearing loss induced by AGs in the early stage.

Show MeSH
Related in: MedlinePlus