In vivo real-time imaging reveals megalin as the aminoglycoside gentamicin transporter into cochlea whose inhibition is otoprotective.
Jinkyung KimAnthony J RicciPublished in: Proceedings of the National Academy of Sciences of the United States of America (2022)
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.
Keyphrases
- quantum dots
- hearing loss
- highly efficient
- visible light
- high resolution
- high glucose
- diabetic rats
- induced apoptosis
- photodynamic therapy
- cell cycle arrest
- oxidative stress
- squamous cell carcinoma
- endothelial cells
- radiation therapy
- drug delivery
- cell proliferation
- cell death
- insulin resistance
- dna binding
- young adults
- high fat diet induced
- binding protein
- positron emission tomography
- stress induced