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Chun-hong Xia, Mei Li, Alex Onishi, Audrey Kim, Xiaohua Gong; Essential role of NHE8 in RPE cell polarity and photoreceptor survival. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2320.
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To test a hypothesis that sodium/proton exchanger 8 (NHE8) plays an essential role in controlling pH homeostasis in the secretory pathway of retinal pigment epithelium (RPE).
Histology and immunohistochemical analysis were performed to study the molecular and cellular alterations in mutant mice; in vitro cell transfection assay and live cell confocal imaging were used to characterize the behavior and subcellular localization of wild-type and mutant NHE8 proteins and their pH regulation; and the in vivo functions of these proteins were investigated by an approach using recombinant adeno-associated virus (r-AAV).
We have found that NHE8, one of the organellar NHEs that regulate medial/trans-Golgi pH and intracellular trafficking and control sodium uptake in the kidney and intestine, is essential for the function of the retina. Both NHE8 knockout and NHE8-M120K point mutant mice develop aberrant RPE with disrupted cell polarity prior to the loss of photoreceptor cells. NHE8 proteins are predominantly colocalized with the Golgi complex and intracellular vesicles in the RPE, and are also expressed in the inner segments of rod photoreceptors. Cell transfection experiments further reveal that both NHE8 and NHE8-M120K proteins are localized in intracellular vesicles. The expression of NHE8-M120K mutant proteins from AAV recombinant virus directly causes abnormal RPE cells and photoreceptor cell death in the wild-type mice.
NHE8 plays an essential role in the function of RPE cells. Mutant NHE8-M120K proteins likely cause pH imbalance of intracellular organelles such as Golgi and endosomes, which disrupting the protein trafficking or recycling to impair the polarity, phagocytosis and other functions of RPE cells and leading to photoreceptor cell death.
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