Hyperosmolarity-induced AQP5 upregulation promotes inflammation and cell death via JNK1/2 Activation in human corneal epithelial cells.
Hyperosmolarity-induced AQP5 upregulation promotes inflammation and cell death via JNK1/2 Activation in human corneal epithelial cells.
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高渗透压诱导的 AQP5 上调通过 JNK1/2 激活人角膜上皮细胞促进炎症和细胞死亡
DOI：
10.1038/s41598-017-05145-y
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发表时间：
2017-07-05
影响因子：
4.6
通讯作者：
Chen W
中科院分区：
文献类型：
--
作者：
Ren Y;Lu H;Reinach PS;Zheng Q;Li J;Tan Q;Zhu H;Chen W
泪膜高渗透压和前眼部炎症是可能表明干眼病（DED）的两种临床症状。这种情况会导致前眼表组织发生病理和功能变化。一个促成因素可能是功能失调的水通道蛋白 5 (AQP5) 水通道，因为它们是在角膜上皮中表达的 AQP 亚型，有助于角膜功能所需的液体流出。我们确定了在原代人角膜上皮细胞 (HCEC) 和 HCEC 细胞系中，所述高渗透压诱导的促炎细胞因子表达和细胞死亡的增加是否是通过 AQP5 上调和 JNK1/2 MAPK 信号激活介导的。实时 RT-PCR 发现，当渗透压逐步增加至 550mOsm 时，IL-1β、IL-6、IL-8、TNF-α、caspase-1 和 AQP5 mRNA 水平升高。 Western blot 分析和 TUNEL 测定分别发现 AQP5 和 p-JNK1/2 蛋白表达和细胞死亡相应增加。 SP600125 抑制 JNK1/2 或 siRNA AQP5 基因沉默可减少高渗诱导的促炎细胞因子表达和细胞死亡的增加。总之，高渗诱导的 AQP5 上调导致促炎细胞因子表达增加，并通过 JNK1/2 MAPK 激活导致细胞死亡。这些结果表明，针对 AQP5 上调的药物可能是 DED 治疗的一种治疗选择。
Tear film hyperosmolarity and anterior ocular inflammation are two clinical signs that may be indicative of dry eye disease (DED). This condition can cause pathological and functional changes to the anterior ocular surface tissues. A contributing factor may be dysfunctional aquaporin 5 (AQP5) water channels as they are the AQP subtype that expressed in the corneal epithelium and contribute to fluid efflux needed for corneal function. We determined if described hyperosmolarity-induced increases in proinflammatory cytokine expression and cell death are mediated through AQP5 upregulation and JNK1/2 MAPK signaling activation in both primary human corneal epithelial cells (HCECs), and in a HCEC line. Real time RT-PCR identified rises in IL-1β, IL-6, IL-8, TNF-α, caspase-1, and AQP5 mRNA levels upon step increases in osmolarity up to 550 mOsm. Western blot analysis and the TUNEL assay identified corresponding rises in AQP5 and p-JNK1/2 protein expression and cell death respectively. JNK1/2 inhibition with SP600125, or siRNA AQP5 gene silencing reduced hypertonic-induced rises in proinflammatory cytokine expression and cell death. Taken together, hypertonicity-induced AQP5 upregulation leads to increases in proinflammatory cytokine expression and cell death through JNK1/2 MAPK activation. These results suggest that drug targeting AQP5 upregulation may be a therapeutic option in DED management.