Department of Otolaryngology, Stanford University School of Medicine, Stanford, CA 94305.
Department of Otolaryngology, Stanford University School of Medicine, Stanford, CA 94305;
Proc Natl Acad Sci U S A. 2022 Mar 1;119(9). doi: 10.1073/pnas.2117946119.
Aminoglycosides (AGs) are commonly used antibiotics that cause deafness through the irreversible loss of cochlear sensory hair cells (HCs). How AGs enter the cochlea and then target HCs remains unresolved. Here, we performed time-lapse multicellular imaging of cochlea in live adult hearing mice via a chemo-mechanical cochleostomy. The in vivo tracking revealed that systemically administered Texas Red-labeled gentamicin (GTTR) enters the cochlea via the stria vascularis and then HCs selectively. GTTR uptake into HCs was completely abolished in transmembrane channel-like protein 1 (TMC1) knockout mice, indicating mechanotransducer channel-dependent AG uptake. Blockage of megalin, the candidate AG transporter in the stria vascularis, by binding competitor cilastatin prevented GTTR accumulation in HCs. Furthermore, cilastatin treatment markedly reduced AG-induced HC degeneration and hearing loss in vivo. Together, our in vivo real-time tracking of megalin-dependent AG transport across the blood-labyrinth barrier identifies new therapeutic targets for preventing AG-induced ototoxicity.
氨基糖苷类（AGs）是常用的抗生素，通过不可逆地丧失耳蜗感觉毛细胞（HCs）而导致耳聋。AGs 如何进入耳蜗，然后靶向 HCs，目前仍未解决。在这里，我们通过化学机械耳蜗切开术对活体成年听力小鼠的耳蜗进行了延时多细胞成像。体内追踪显示，系统给予的 Texas Red 标记的庆大霉素（GTTR）通过血管纹进入耳蜗，然后选择性地进入 HCs。TMC1 敲除小鼠中的 GTTR 进入 HCs 被完全阻断，表明 AG 摄取依赖于跨膜通道样蛋白 1（TMC1）。通过结合竞争抑制剂西拉他汀阻断血管纹中的候选 AG 转运体巨球蛋白，可防止 GTTR 在 HCs 中积累。此外，西拉他汀处理显著减少了体内 AG 诱导的 HCs 变性和听力损失。总之，我们对 megalin 依赖性 AG 跨血迷路屏障转运的体内实时追踪为预防 AG 诱导的耳毒性提供了新的治疗靶点。
