Loss of NHE8 expression impairs ocular surface function in mice.
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.
Department of Pediatrics, Steele Children's Research Center, University of Arizona College of Medicine, Tucson, Arizona;
Hua
H
Xu
Department of Pediatrics, Steele Children's Research Center, University of Arizona College of Medicine, Tucson, Arizona; Department of Ophthalmology, Shenyang Northern Hospital, Shenyang, People's Republic of China.
Yang
Y
Zhao
Department of Pediatrics, Steele Children's Research Center, University of Arizona College of Medicine, Tucson, Arizona;
Jing
J
Li
Department of Ophthalmology and Vision Science, University of Arizona College of Medicine, Tucson, Arizona;
Mingwu
M
Wang
Department of Pathology, University of Arizona College of Medicine, Tucson, Arizona; and.
Fangru
F
Lian
Department of Ophthalmology, Shenyang Northern Hospital, Shenyang, People's Republic of China.
Minghong
M
Gao
Department of Pediatrics, Steele Children's Research Center, University of Arizona College of Medicine, Tucson, Arizona; fghishan@peds.arizona.edu.
Fayez K
FK
Ghishan
D000818:Animals; D017920:Antiporters / Q000235:genetics / Q000378:metabolism; D003228:Conjunctiva / Q000378:metabolism / Q000473:pathology; D003315:Cornea / Q000378:metabolism / Q000473:pathology; D055233:Cornified Envelope Proline-Rich Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005123:Eye / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005838:Genotype; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007765:Lacrimal Apparatus / Q000378:metabolism / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D018345:Mice, Knockout; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism*; D000076988:Sulfate Transporters; D013666:Tears / Q000378:metabolism; D011503:Transglutaminases / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D017920:Antiporters; D055233:Cornified Envelope Proline-Rich Proteins; D012333:RNA, Messenger; C486775:SLC9A8 protein, human; C489860:Slc26a3 protein, mouse; C471945:Slc9a8 protein, mouse; D017923:Sodium-Hydrogen Exchangers; C491980:Sprr2h protein, mouse; D000076988:Sulfate Transporters; D014409:Tumor Necrosis Factor-alpha; D011503:Transglutaminases; C105804:transglutaminase 1; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
NHE8; conjunctiva; cornea; epithelia; lacrimal gland