Abstract
Fluid and solute transporters of the retinal pigment epithelium (RPE) are core components of the outer blood–retinal barrier. Characterizing these transporters and their role in retinal homeostasis may provide insights into ocular function and disease. Here, we describe RPE defects in tvrm77 mice, which exhibit hypopigmented patches in the central retina. Mapping and nucleotide sequencing of tvrm77 mice revealed a disrupted 5’ splice donor sequence in Slc4a5, a sodium bicarbonate cotransporter gene. Slc4a5 expression was reduced 19.7-fold in tvrm77 RPE relative to controls, and alternative splice variants were detected. SLC4A5 was localized to the Golgi apparatus of cultured human RPE cells and in apical and basal membranes. Fundus imaging, optical coherence tomography, microscopy, and electroretinography (ERG) of tvrm77 mice revealed retinal detachment, hypopigmented patches corresponding to neovascular lesions, and retinal folds. Detachment worsened and outer nuclear layer thickness decreased with age. ERG a- and b-wave response amplitudes were initially normal but declined in older mice. The direct current ERG fast oscillation and light peak were reduced in amplitude at all ages, whereas other RPE-associated responses were unaffected. These results link a new Slc4a5 mutation to subretinal fluid accumulation and altered light-evoked RPE electrophysiological responses, suggesting that SLC4A5 functions at the outer blood–retinal barrier.
Highlights
The transport of nutrients, electrolytes, gases, water, and waste products between the retina and the systemic circulation is regulated by the blood–retinal barrier (BRB) [1].Disruption of the BRB affects retinal homeostasis and visual function [2] and is implicated in major ocular diseases [3,4,5]
Solute, and water transport are coordinated on short timescales to maintain an ionic environment suitable for photoreceptor signaling and recovery following light stimuli and on longer timescales to ensure a close apposition of outer segments with retinal pigment epithelium (RPE) apical processes, which is required for photoreceptor homeostasis
SLC4A5 protein was expressed in RPE cells, we examined two lines of pluripotent stem (WA09 human embryonic stem cell, hESC; A04, human induced pluripotent stem cell, cells (WA09 human embryonic stem cell, hESC; A04, human induced pluripotent stem hiPSC)
Summary
The transport of nutrients, electrolytes, gases, water, and waste products between the retina and the systemic circulation is regulated by the blood–retinal barrier (BRB) [1].Disruption of the BRB affects retinal homeostasis and visual function [2] and is implicated in major ocular diseases [3,4,5]. In most mammals, including humans and mice, the interface between the retina and circulation consists of two components: the inner BRB, which mediates transport between cells of the inner retina and the retinal vasculature, and the outer BRB, which mediates transport between the photoreceptor outer segments and the choroidal vascular bed (choriocapillaris). An essential component of the outer BRB is the retinal pigment epithelium (RPE), an epithelial monolayer that lies between the outer segments of the retina and the vascular endothelial cells of the choriocapillaris [1,6,7,8]. A core function of the RPE is to regulate subretinal fluid composition, which depends on the selective transport of ions and other solutes to and from this compartment, as well as on the transport of water to the choriocapillaris [1,6,7,8,9,10]. Physiological and pharmacological studies of vertebrate tissues and cultured cells have demonstrated that ATP-dependent transport of Na+ and
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