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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,3]]},"abstract":"<jats:p>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\u00a0vivo tracking revealed that systemically administered Texas Red\u2013labeled 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\u00a0vivo. Together, our in\u00a0vivo real-time tracking of megalin-dependent AG transport across the blood\u2013labyrinth barrier identifies new therapeutic targets for preventing AG-induced ototoxicity.<\/jats:p>","DOI":"10.1073\/pnas.2117946119","type":"journal-article","created":{"date-parts":[[2022,2,23]],"date-time":"2022-02-23T17:45:58Z","timestamp":1645638358000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":37,"title":["In vivo real-time imaging reveals megalin as the aminoglycoside gentamicin transporter into cochlea whose inhibition is otoprotective"],"prefix":"10.1073","volume":"119","author":[{"given":"Jinkyung","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Otolaryngology, Stanford University School of Medicine, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1706-8904","authenticated-orcid":false,"given":"Anthony J.","family":"Ricci","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Stanford University School of Medicine, Stanford, CA 94305"},{"name":"Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2022,2,23]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.1336"},{"key":"e_1_3_4_2_2","volume-title":"Critically Important Antimicrobials for Human Medicine","author":"Organization World Health","year":"2019","unstructured":"World Health Organization, Critically Important Antimicrobials for Human Medicine (WHO Document Production Services, 2019)."},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/ar.22578"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(14)70780-7"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/0378-5955(85)90121-2"},{"key":"e_1_3_4_6_2","volume-title":"An Introduction to the Physiology of Hearing","author":"Pickles J. 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