Fluid and solute transport across the retinal pigment epithelium: a theoretical model

Abstract

<jats:p> The retina is composed of two main layers—the neuroretina and the retinal pigment epithelium (RPE)—that are separated by a potential gap termed the sub-retinal space (SRS). Accumulation of fluid in the SRS may result in a retinal detachment. A key function of the RPE is to prevent fluid accumulation in the SRS by actively pumping fluid from this space to the choroid. We have developed a mathematical model of this process that incorporates the transport of seven chemical species: Na <jats:sup>+</jats:sup> , K <jats:sup>+</jats:sup> , Cl <jats:sup>−</jats:sup> , <jats:inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"> <mml:msubsup> <mml:mtext>HCO</mml:mtext> <mml:mn>3</mml:mn> <mml:mo>−</mml:mo> </mml:msubsup> </mml:math> </jats:inline-formula> , H <jats:sup>+</jats:sup> , CO <jats:sub>2</jats:sub> and H <jats:sub>2</jats:sub> CO <jats:sub>3</jats:sub> . This allows us to estimate solute and water fluxes and to understand the role of the different membrane ion channels. We have performed a global sensitivity analysis using the extended Fourier amplitude sensitivity test to investigate the relative importance of parameters in generating the model outputs. The model predicts that flow across the RPE is driven by an osmotic gradient in the cleft gap between adjacent cells. Moreover, the model estimates how water flux is modified in response to inhibition of membrane ion channels and carbonic anhydrase (CA). It provides a possible explanation for how CA inhibitors, which are used clinically to prevent fluid accumulation in the SRS, may be acting. </jats:p>

Application of an organotypic ocular perfusion model to assess intravitreal drug distribution in human and animal eyes

“…However, it is important to note that the influence of EVP and retinal vascular flow and leakage, as well as daily fluctuations in IOP, is not represented in this model at present. Similarly, the potential influence of subretinal fluid pumping by the retinal pigmented epithelium has not yet been assessed [ 81 ]. EVP makes important contributions to IOP in vivo and is a key term of the modified Goldmann equation used to calculate outflow [ 82 , 83 ].…”

A Splicing Mutation in Slc4a5 Results in Retinal Detachment and Retinal Pigment Epithelium Dysfunction

“…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]. Ion, 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 RPE apical processes, which is required for photoreceptor homeostasis.…”

“…Water transport is secondary to net ion efflux from the RPE, mainly of K + and Cl − ; other major solutes of the subretinal space that influence water efflux include H + , CO 2 , H 2 CO 3 , HCO 3 − , and lactate. Further, a number of RPE proteins are known or postulated to mediate solute and water transport, such as the apical Na + , K + ATPase, potassium channel KCNJ13 (Kir7.1), Na + -K + -2Cl − cotransporter, and Na + -H + antiporter; basolateral chloride channels CFTR, BEST1, and CLCN2 (ClC-2) and the Cl − -HCO 3 − exchanger SCL4A2 (AE2); apical and basolateral AQP1 (aquaporin), monocarboxylate transporters MCT1 and MCT3, and sodium bicarbonate cotransporters; and intracellular carbonic anhydrase, which converts dissolved CO 2 gas to H 2 CO 3 [1,[6][7][8][9][10]. However, uncertainties remain about the contribution of these specific transporters and channels to RPE ion, solute, and water transport in vivo, which may benefit from studying animal models that disrupt them.…”

“…Physiological studies of frog, bovine, human, and cultured human RPE have identified a system of integral membrane transporters and intracellular enzymes responsible for net movement of HCO 3 − and H 2 O from the subretinal space to the choroidal circulation [7][8][9]70,71]. This system is postulated to remove excess CO 2 and H 2 O generated by the high metabolic activity of photoreceptor cells, maintaining a negative hydrostatic pressure that ensures tight adhesion of the retina to the RPE apical surface.…”

“…This system is postulated to remove excess CO 2 and H 2 O generated by the high metabolic activity of photoreceptor cells, maintaining a negative hydrostatic pressure that ensures tight adhesion of the retina to the RPE apical surface. The functional importance of an electrogenic basolateral sodium bicarbonate cotransporter to this system was established by physiological studies [70] and further supported by mathematical modeling [9]. SLC4A4 (NBC1) and SLC4A5 were considered as candidates for this transporter based on high levels of the corresponding transcripts in native and cultured human RPE [70,72].…”