ENaC蛋白表达上调引起内淋巴水钠代谢紊乱诱发膜迷路积水

膜迷路积水是梅尼埃病的重要病理学特征。既往研究表明，梅尼埃病患者血抗利尿激素（ADH）及醛固酮（ALD）水平均明显升高，但单纯应用利尿剂不能完全控制梅尼埃病眩晕发作。在泌尿系统中，ADH及ALD共同调节水钠平衡。上皮钠通道蛋白（ENaC）是ADH及ALD调节水钠平衡的关键靶点蛋白，但ENaC在膜迷路积水的形成过程中的作用尚不明确。本项目组前期研究发现ADH诱发膜迷路积水的豚鼠模型中，内淋巴囊上皮细胞的ENaC表达水平升高，表达水平与膜迷路积水严重程度正相关，因此我们提出假说：外源性ADH及ALD升高使ENaC表达上调引起钠离子转运失衡造成水钠潴留导致膜迷路积水。本项目通过基因敲除及应用ENaC拮抗剂调控ENaC表达的动物模型，观察给予外源性ADH和ALD干预前后听觉电生理、形态学及平衡功能的变化，探索ENaC在ALD和ADH造成膜迷路积水的作用及机制，为治疗梅尼埃病提供新的治疗靶点。

The pathology of Meniere's disease (MD) is well established to be endolymphatic hydrops. Previous studies have shown that the levels of antidiuretic hormone (ADH) and aldosterone (ALD) in peripheral blood of patients with Meniere's disease are significantly increased, but diuretics alone cannot control vertigo in MD. In the urinary system, ADH and ALD can jointly regulate the balance of water and sodium and Epithelial sodium channel (ENaC) is one of key target proteins for ADH and ALD to regulate water and sodium balance. However, the role of ENaC in the formation of endolymphatic hydrops is not clear. Our recent data showed that the expression of ENaC in endolymphatic sac epithelial cells increased in the guinea pig model of endolymphatic hydrops induced by ADH, and the expression level was positively correlated with the severity of endolymphatic hydrops, Based on these studies, we hypothesized that the increase of serum ALD and ADH leads to the up-regulation of ENaC expression, and consequently causing imbalance of sodium transport, water and sodium retention, leading to endolymphatic hydrops. Accordingly, the role of ENaC in the formation of endolymphatic hydrops using gene knock-in and knock-out were evaluated before and after exposure to ADH and ALD in adult mice, and the protective effects id ENaC antagonists against endolymphatic hydrops were explored. We sought to determine whether up-regulation of ENaC expression leads to endolymphatic hydrops and the pothetial mechanism. Together, this study strongly supports ENaC as a potential therapeutic target with the potential to inhibit endolymphatic hydrops in patients with MD.