Chen Jun, Yuan Hu, Talaska Andra E, Hill Kayla, Sha Su-Hua
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Walton Research Building, Room 403-E, 39 Sabin Street, Charleston, SC, 29425, USA,
J Assoc Res Otolaryngol. 2015 Jun;16(3):347-56. doi: 10.1007/s10162-015-0508-x. Epub 2015 Mar 20.
The PI3K/Akt signaling pathway is involved in mediating survival of sensory hair cells. Here, we investigated the involvement of PI3K/Akt in noise-induced hearing loss in both temporary and permanent threshold shift noise models. The PI3K regulatory subunit p85α and phosphorylation of Akt on serine 473 (p-Akt S473) are downregulated in sensory hair cells, including both outer and inner hair cells, and supporting cells of the mouse organ of Corti 1 h after exposure to permanent-threshold-shift-inducing noise (PTS noise), but not with temporary-threshold-shift-inducing noise (TTS noise). In contrast, the PI3K catalytic subunit p110α and phosphorylation of Akt on threonine 308 (p-Akt T308) do not change with PTS or TTS noise. Additionally, mice pretreated with p85α small interfering RNA (siRNA) have decreased expression of p-Akt1 (S473) in their sensory hair cells and increased sensitivity to TTS noise-induced hearing loss. Finally, Akt1-knockout mice also have enhanced sensitivity to TTS noise-induced hearing loss. In conclusion, this study suggests that endogenous PI3K/Akt signaling is an intrinsic protective mechanism of the inner ear. Blockade of PI3K/Akt signaling pathways increases sensitivity to TTS noise-induced hearing loss.
PI3K/Akt信号通路参与介导感觉毛细胞的存活。在此，我们在临时和永久性阈移噪声模型中研究了PI3K/Akt在噪声性听力损失中的作用。在暴露于永久性阈移诱导噪声（PTS噪声）1小时后，PI3K调节亚基p85α以及丝氨酸473位点的Akt磷酸化（p-Akt S473）在小鼠柯蒂氏器的感觉毛细胞（包括外毛细胞和内毛细胞）及支持细胞中下调，但在暴露于临时阈移诱导噪声（TTS噪声）后未出现这种情况。相比之下，PI3K催化亚基p110α以及苏氨酸308位点的Akt磷酸化（p-Akt T308）在PTS或TTS噪声作用下均未改变。此外，用p85α小干扰RNA（siRNA）预处理的小鼠，其感觉毛细胞中p-Akt1（S473）的表达降低，并且对TTS噪声诱导的听力损失的敏感性增加。最后，Akt1基因敲除小鼠对TTS噪声诱导的听力损失也更敏感。总之，本研究表明内源性PI3K/Akt信号是内耳的一种内在保护机制。阻断PI3K/Akt信号通路会增加对TTS噪声诱导的听力损失的敏感性。
