Loss of NHE8 expression impairs ocular surface function in mice

Abstract

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.

MouseSlc9a8Mutants Exhibit Retinal Defects Due to Retinal Pigmented Epithelium Dysfunction

“…13,15 Furthermore, it has been reported recently that the gene is expressed in the epithelial cells of the conjunctiva, cornea, and lacrimal glands and may have a role in the protection of these ocular epithelia. 16 The male mutants also are sterile.…”

SLC9 Gene Family: Function, Expression, and Regulation

“…Mice with targeted ablation of the Slc9a8 gene showed that gastric expression of NHE8 was critical for the maintenance of bicarbonate secretion by the Cl − /HCO 3 − exchanger downregulated-in-adenoma (DRA; Slc26a3 ), and that compared with their wild-type littermates, Nhe8 -deficient mice had a higher incidence of gastric ulcer formation (315). Although the mechanism responsible for downregulation of DRA expression remains unknown, it appears to be a phenomenon consistent across organs as it was also described in the colon (321), conjunctiva, cornea, and the lacrimal glands (322). …”

Pathophysiology of Intestinal Na+/H+ Exchange

“…Compared with their wild-type littermates, mice lacking NHE8 had a higher incidence of gastric ulcer formation 32 . Although the mechanism responsible for DRA down-regulation is not yet clear, it appears to be a phenomenon consistent across organs because it was described also in the colon, 41 conjunctiva, the cornea, and the lacrimal glands 42 …”