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Mark D Parker, Sangita P Patel, Aniko Marshall, Cheikh Mballo, Emily E Salerno; A novel model of corneal edema in mice with a disrupted endothelial bicarbonate transporter. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5655.
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© ARVO (1962-2015); The Authors (2016-present)
The bicarbonate transporter NBCe1 is expressed in corneal endothelial cells (CECs) where it supports endothelial fluid transport and thereby contributes to control of corneal hydration and prevention of edema. NBCe1 loss in humans results in proximal renal tubular acidosis with ocular abnormalities: a combination of band keratopathy, cataracts, and glaucoma in addition to a low blood pH that follows the concurrent loss of the renal isoform of NBCe1. To study the importance of NBCe1 to corneal health, in the absence of complications from systemic pH imbalance, we have generated a novel strain of conditional NBCe1-knockout mice. These mice have been engineered to retain renal expression of NBCe1, but to lack NBCe1 expression elsewhere. We hypothesized that these mice should exhibit corneal edema.
We studied male and female wild-type (WT) and knockout (KO) mice at 6-7 weeks of age. We measured blood pH using a handheld blood-analysis system. We assessed the central corneal thickness (CCT) of live mice using an ultrasonic pachymeter. We performed immunohistochemical analysis on sections of mouse eye and kidney to examine the presence or absence of NBCe1 and other membrane proteins important for maintaining corneal hydration.
In KOs, renal NBCe1 expression and blood pH are normal. As expected, NBCe1 is absent from KO CECs. In WTs, CCT is 109 ± 4 µm (mean ± SEM, n=4), in KOs CCT is significantly greater 138 ± 4 µm (n=7; P=0.002, t-test), an observation consistent with our hypothesis. Unexpectedly, we find the expression of two other determinants of endothelial function to be disturbed in KOs: the H+/lactate cotransporter MCT1 is absent from KO CECs and the usually basolateral Na+,K+-ATPase appears to be mislocalized to the apical membrane.
NBCe1 loss results in corneal edema in the anatomical presence of corneal endothelial cells. However, disturbed expression of other endothelial transporters in KOs indicates that, beyond the intrinsic transport activity of NBCe1, the protein plays an additional role in coordinating the expression of other components of the corneal hydration mechanism. Our model also suggests that mutations in NBCe1 that specifically affect non-renal NBCe1 could underlie rare instances of endothelial dystrophy for which the molecular basis is not known.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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