Loss of NHE8 expression impairs ocular surface function in mice.
Loss of NHE8 expression impairs ocular surface function in mice.
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NHE8 表达缺失会损害小鼠眼表功能。
DOI：
10.1152/ajpcell.00296.2014
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发表时间：
2015
期刊：
影响因子：
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通讯作者：
Ghishan,FayezK
中科院分区：
文献类型：
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作者：
Xu,Hua;Zhao,Yang;Li,Jing;Wang,Mingwu;Lian,Fangru;Gao,Minghong;Ghishan,FayezK
钠/氢交换器（NHE）8在上皮细胞的顶膜处表达，并且在胃肠道和肾脏中的中性钠吸收中起重要作用。它还在胃腺和肠的上皮粘膜保护中起重要作用。虽然NHE 8具有广泛的组织分布，但NHE 8在眼睛中的精确位置和生理作用仍然未知。在本研究中，我们成功地检测了NHE 8在人和小鼠眼表的表达，通过PCR和Western blot。免疫组织化学染色显示，人和小鼠的结膜、角膜和泪腺上皮细胞的质膜上都有NHE 8蛋白。我们还检测到在眼表上皮细胞中下调的腺瘤蛋白（C1-/HCO 3-转运蛋白）的表达。使用NHE 8 −/−小鼠模型，我们发现NHE 8功能的丧失导致泪液产生减少和角膜染色增加。这些NHE 8 −/−小鼠也显示TNF-α和基质金属蛋白酶9（MMP 9）基因的表达增加。上皮角化标记基因，富含脯氨酸的小蛋白2 h（Sprr 2 h）和转氨酶1（Tgm 1）的表达也在NHE 8 −/−眼中增加。此外，NHE 8 −/−小鼠的结膜、角膜和泪腺中的NHE 8表达减少，这与结膜粘膜pH值降低有关。NHE 8 −/−小鼠的眼表功能改变和上皮细胞NHE 8表达减少表明，NHE 8在眼表组织中的作用涉及泪液产生和眼上皮保护。这项研究揭示了干眼症的一个潜在的新机制，涉及异常NHE 8功能。
Sodium/hydrogen exchanger (NHE) 8 is expressed at the apical membrane of the epithelial cells and plays important roles in neutral sodium absorption in the gastrointestinal tract and the kidney. It also has an important role in epithelial mucosal protection in the gastric gland and the intestine. Although NHE8 has broad tissue distribution, the precise location and the physiological role of NHE8 in the eye remain unknown. In the present study, we successfully detected the expression of NHE8 in the ocular surface by PCR and Western blot in human and mouse eyes. Immunohistochemistry staining located NHE8 protein at the plasma membrane of the epithelial cells in the conjunctiva, the cornea, and the lacrimal gland both in human and mouse. We also detected the expression of downregulated-in-adenoma (DRA, a Cl−/HCO3−transporter) in the ocular surface epithelial cells. Using NHE8−/− mouse model, we found that loss of NHE8 function resulted in reduced tear production and increased corneal staining. These NHE8−/− mice also showed increased expression of TNF-α and matrix metalloproteinase 9 (MMP9) genes. The expression of epithelial keratinization marker genes, small proline-rich protein 2h (Sprr2h) and transglutaminase 1 (Tgm1), were also increased in NHE8−/− eyes. Furthermore, DRA expression in NHE8−/− mice was reduced in the conjunctiva, the cornea, and the lacrimal glands in association with a reduction in conjunctival mucosal pH. Altered ocular surface function and reduced epithelial DRA expression in NHE8−/− mice suggest that the role of NHE8 in ocular surface tissue involve in tear production and ocular epithelial protection. This study reveals a potential novel mechanism of dry eye condition involving abnormal NHE8 function.