ABCC1缺陷通过NOX2/ROS轴介导对镉诱导听力损失的易感性。

文献信息

中文摘要

镉（Cd）是一种普遍存在的环境污染物，与听觉功能障碍相关。耳蜗血-迷路屏障（BLB）保护内耳免受有毒物质侵害，在这一过程中，ATP结合盒亚家族C成员1蛋白ABCC1在其细胞排出毒素方面发挥关键作用。为了解ABCC1对镉诱导听力损伤的具体贡献，我们采用了体内模型（ABCC1敲除小鼠，Abcc1 -/-小鼠）和体外内皮模型（ABCC1缺陷的人脐静脉内皮细胞，ABCC1 -/-HUVECs）。这些模型暴露于CdCl2，以评估听觉反应、组织病理学、BLB完整性和氧化应激。我们还使用免疫荧光、Western印迹和RNA-seq分析探索了NOX2-ROS/PI3K-AKT通路。结果表明，ABCC1缺陷加剧了镉诱导的BLB渗漏，促进了螺旋神经节神经元和突触前带斑点丢失，并增加了ABR阈值。在动物和细胞模型中，ABCC1缺陷增强了NOX2表达、ROS积累和AKT去磷酸化。值得注意的是，用GSK2795039对NOX2进行药理学抑制可减轻氧化应激、保留内皮屏障功能，并部分恢复PI3K-AKT信号传导。这些发现表明，ABCC1是镉暴露期间耳蜗血管完整性的关键保护因子，通过NOX2-ROS/PI3K-AKT轴发挥作用，并提示其作为预防镉诱导听力损失治疗靶点的潜力。

英文摘要

Cadmium (Cd), a prevalent environmental contaminant, is associated with auditory dysfunction. The cochlear blood-labyrinth barrier (BLB) protects the inner ear from toxic substances, a process in which the ATP-binding cassette subfamily C member 1 protein, ABCC1, plays a critical role in expelling toxins from its cells. To understand the specific contribution of ABCC1 to Cd-induced hearing damage, we employed both an in vivo model (ABCC1 knockout mice, Abcc1 -/- mice) and an in vitro endothelial model (ABCC1-deficient human umbilical vein endothelial cells, ABCC1 -/-HUVECs). These models were exposed to CdCl2 to assess auditory responses, histopathology, BLB integrity, and oxidative stress. We also explored the NOX2-ROS/PI3K-AKT pathway using immunofluorescence, Western blotting, and RNA-seq analyses. The results indicate that ABCC1 deficiency exacerbated Cd-induced BLB leakage, promoted spiral ganglion neurons and presynaptic ribbon puncta loss, and increased ABR thresholds. In both animal and cellular models, ABCC1 deficiency enhanced NOX2 expression, ROS accumulation, and AKT dephosphorylation. Significantly, pharmacological inhibition of NOX2 with GSK2795039 attenuated oxidative stress, preserved endothelial barrier function, and partially restored PI3K-AKT signaling. These findings identify ABCC1 as a critical protector of cochlear vascular integrity during Cd exposure, acting through the NOX2-ROS/PI3K-AKT axis, and suggest its potential as a therapeutic target for preventing Cd-induced hearing loss.