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Stanford University

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Proc. Natl. Acad. Sci. USA, February 23, 2022, 119 (9) e2117946119 | https://doi.org/10.1073/pnas.2117946119 In vivo real-time imaging reveals megalin as the aminoglycoside gentamicin transporter into cochlea whose inhibition is otoprotective

Jinkyung Kim^a and Anthony J. Ricci^a,b,1

^aDepartment of Otolaryngology, Stanford University School of Medicine, Stanford, CA 94305; and ^bDepartment of Molecular and Cellular Physiology, StanfordUniversity School of Medicine, Stanford, CA 94305

¹To whom correspondence may be addressed.

Abstract

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.

논문정보

형식Research article
게재일2022년 02월 (BRIC 등록일 2022-03-11)
연구진국외 연구진
분야 의약학 > 신경의학

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