MiR-34a contributes to diabetes-related cochlear hair cell apoptosis via SIRT1/HIF-1α signaling

Abstract

Type 2 diabetes (T2DM) has been considered to be associated with a higher likelihood of hearing impairment (HI). However, the molecular mechanisms underlying the association between diabetes and HI are poorly understood. MicroRNAs have recently been demonstrated to be closely associated with hearing loss and considered as promising therapeutic targets. Herein, we investigated whether miR-34a contributes to diabetes-related cochlear hair cell apoptosis and sought to identify the underlying mechanism. The results showed that miR-34a was up-regulated in the cochleas of db/db mice, accompanied by significant hearing threshold elevation and hair cell loss. However, the expression of SIRT1 was significantly down-regulated, while hypoxia-inducible factor-1alpha (HIF-1α) levels were dramatically increased in the cochleas of db/db mice. In addition, in the high-glucose cultured House Ear Institute-Organ of Corti 1 (HEI-OC1) cell line, miR-34a overexpression inhibited sirtuin1 (SIRT1) expression, increased HIF-1α levels and promoted apoptosis. MiR-34a knockdown exerted effects that were diametrically opposed to those observed with overexpression. Interestingly, HIF-1α knockdown almost eliminated the cell apoptosis induced by high glucose levels. We also examined the modulation of HIF-1α expression by SIRT1. The results showed that SIRT1 knockdown further promoted high-glucose-induced HIF-1α expression, while SIRT1 overexpression significantly inhibited HIF-1α level induced by high glucose. These findings point to a new mechanism by which miR-34a exerts its detrimental effects by negatively regulating SIRT1/HIF-1α signaling and provide new therapeutic targets for treating hearing impairment during diabetes.