Upregulation of TRPV2 exacerbates age-related hearing loss by promoting oxidative stress in spiral ganglion neurons.

Abstract

Age-related hearing loss (ARHL) is a prevalent neurodegenerative condition characterized by the progressive loss of spiral ganglion neurons (SGNs). Although oxidative stress is recognized as a central pathogenic driver of ARHL, the precise molecular triggers that initiate and amplify SGN damage remain elusive. Here, we investigated the role of the Transient Receptor Potential Vanilloid 2 (TRPV2) channel in ARHL. We found that TRPV2 expression was significantly upregulated in the SGNs of aged mice, which was associated with elevated oxidative stress. Pharmacological activation of TRPV2 in 6-month-old mice (a pre-senescent stage with preserved baseline hearing) accelerated the onset of high-frequency hearing damage, as evidenced by auditory brainstem response (ABR) measurements. Consistently, TRPV2 activation exacerbated oxidative damage (assessed by 4-HNE staining) and increased apoptotic cell death (detected via TUNEL) in the SGN population. In primary SGN cultures, TRPV2 overexpression aggravated oxidative stress, whereas TRPV2 knockdown in SH-SY5Y cells (a human neuroblastoma cell line) markedly mitigated the oxidative injury as reflected by reduced 4-HNE. Our findings establish that the age-related upregulation of TRPV2 sensitizes SGNs to oxidative stress, thereby promoting neuronal damage and exacerbating ARHL. This work highlights TRPV2 as a promising therapeutic target for intervening in the progression of ARHL.