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Molecular Solutions to Mammalian Lens Transparency

Paul Donaldson, Joerg Kistler and Richard T. Mathias

P. Donaldson is in the Department of Physiology, School of Medicine, and J. Kistler is in the School of Biological Sciences, University of Auckland, Auckland, New Zealand. R. T. Mathias is in the Department of Physiology and Biophysics, State University of New York at Stony Brook, Stony Brook, New York 11794-8661.

	Abstract

 
The mammalian lens generates an internal microcirculation that maintains transparency in the avascular lens. Significant progress has been made in characterizing the membrane transport proteins associated with this circulation. By combining physiological and molecular evidence, a more comprehensive understanding of normal lens function and cataractogenesis is emerging.

	Introduction

Top Introduction An internal circulation... Na+, water, and glucose... Gap junctions play a... New insights into lens... Future outlook References

 
The ability of the ocular lens to focus light on the retina is the result of a unique cellular physiology and tissue architecture that eliminates light scattering and improves the optical properties of the lens. The lens is an avascular tissue surrounded by a tough but porous collagenous capsule (Fig. 1A). Beneath the capsule, a single layer of cuboidal epithelial cells covers the anterior surface. At the equator, these epithelial cells divide and the daughter cells elongate and differentiate into the fiber cells, which form the bulk of the lens. The fiber cells adopt a flattened hexagonal profile that facilitates packing into an ordered array with spaces between the cells smaller than the wavelength of light. During differentiation, the fiber cells lose their intracellular organelles and undergo significant changes in the expression of cytoplasmic and membrane proteins. An overabundance of soluble cytoplasmic proteins, called crystallins, creates a high index of refraction. This concentration of crystallins is highest in the center of the lens and creates a radial gradient in refractive index that corrects inherent spherical aberration. Lens growth continues throughout the lifetime of an individual, with younger fiber cells being laid down on top of existing fiber cells, resulting in the progressive positioning of older cells deeper into the lens. Each mature fiber cell extends from the anterior to the posterior pole, where it forms a suture with other fiber cells.

View larger version (54K): [in this window] [in a new window]   FIGURE 1. Structure and function of the mammalian lens. A: architecture of the lens showing the anterior epithelial monolayer, elongating nucleated fiber cells, cortical fiber cells, and mature fiber cells (MF) in the lens nucleus. DF, differentiating fibers. B: current flow through the lens that underpins the internal circulation system (scheme redrawn from Ref. 8). C: representative cross-section taken through the lens equator. Current and solutes are proposed to flow into the lens via the extracellular space, to cross fiber cell membranes, and to flow outward via an intracellular pathway mediated by gap junction channels. E, epithelial cells.

It follows from the above that the lens needs a specialized transport system that delivers nutrients, removes waste products, and imposes the negative membrane potential required to maintain the steady-state volume of the fiber cells. A common feature of all vertebrate lenses studied to date is the existence of a standing flow of ionic current that is directed inward at the poles and outward at the equator (Fig. 1B). Mathias et al. (10) suggested that this standing current generates a unique internal microcirculatory system that is responsible for maintaining fiber cell homeostasis and therefore lens transparency. This review summarizes new results supportive of such a system.

	An internal circulation maintains lens transparency

Top Introduction An internal circulation... Na+, water, and glucose... Gap junctions play a... New insights into lens... Future outlook References

 
The circulating currents and theoretical work on modeling the transport properties of the lens have recently been reviewed (10), and only a summary is provided here. Briefly, the working model is that the current, which is carried primarily by Na⁺, enters at all locations around the lens along the extracellular clefts between fiber cells. It eventually crosses the fiber cell membranes, then flows from cell to cell toward the surface via an intracellular pathway mediated by gap junction channels. Because the gap junction channels in the outer shell of differentiating fibers (Fig. 1A) are concentrated at the equator, the intracellular current is directed to the equatorial surface cells where the Na⁺-K⁺ pumps are concentrated. There the Na⁺ is transported out of the lens. Thus at the equator the intracellular current that is leaving the lens is highly concentrated, causing the net current to be outward, whereas at the poles there is very little intracellular current, so the net current is predominantly inward along the extracellular spaces. The resulting lines of net current flow are shown in Fig. 1B.

The driving force for these fluxes is hypothesized to be the difference in the electromotive potential of surface cells and inner fiber cells. Data reviewed in Mathias et al. (10) suggest that the surface cells, including epithelial cells and newly differentiating fiber cells, contain Na⁺-K⁺ pumps and K⁺ channels, which together generate a negative electromotive potential. Fiber cells deeper in the lens lack functional Na⁺-K⁺ pumps and K⁺ channels. Instead, their permeability is dominated by Na⁺ and Cl^– leak conductances whose molecular identities remain to be determined. In these inner cells a negative membrane potential is maintained by being connected with the surface cells via gap junctions. This electrical connection, together with the different membrane properties of the surface and inner cells, causes the standing current to flow.

In this model, the circulating current creates a net flux of solute that generates fluid flow. The extracellular flow of water convects nutrients toward the deeper-lying fiber cells, whereas the intracellular flow removes wastes and creates a well-stirred intracellular compartment. Thus transport by surface cells is able to regulate the ion composition of inner fiber cells and allows them to maintain constant volume. Together, these factors allow the lens to maintain transparency. For this model to be correct, fiber cell and surface cell membranes need significant water permeability, the fiber cells need a mechanism of importing the glucose that is being convected to them, and the equatorial surface cells need a mechanism of exporting the flux of Na⁺ that is arriving from the inner fiber cells.

	Na+, water, and glucose transport in the lens have been characterized

Top Introduction An internal circulation... Na+, water, and glucose... Gap junctions play a... New insights into lens... Future outlook References

 
Na⁺-K⁺ pumps.
The only known mechanism for normal export of Na⁺ from a cell is via the Na⁺-K⁺ pumps in the plasma membrane. Thus if the circulation model is correct, the lens needs to concentrate its Na⁺-K⁺ pumps in the equatorial surface cells to export the large intracellular flux of Na⁺ flowing to the equatorial surface from the mass of fiber cells. Recent studies (4) have shown that the Na⁺-K⁺ pumps are indeed so localized. Anterior epithelial cells, equatorial epithelial cells, and equatorial differentiating cells were acutely isolated from the frog lens and separately studied by using the whole cell patch-clamp method. The Na⁺-K⁺ pump current density was about twice as large in the equatorial cells compared with anterior epithelial cells. In addition, the equatorial differentiating cells were much larger than the anterior cells, and several layers of differentiating equatorial fiber cells contribute to whole lens Na⁺-K⁺ pump activity. On the basis of these measurements, Gao et al. (4) estimated that the total Na⁺-K⁺ pump activity per unit area of lens surface was ~20 times larger at the equator than at the anterior pole.

In addition to an increased number of Na⁺-K⁺ pumps at the equator relative to the poles, there is also a change in its molecular composition (4). The Na⁺-K⁺ pump is composed of an - and a ß-subunit, with the -subunit performing all of the known transport functions (reviewed in Ref. 9). There are at least three isoforms of the -subunit, and the frog lens preferentially expresses the ₂-isoform at the anterior pole and the ₁-isoform at the equator (4). Mathias et al. (9) reported that, in guinea pig heart, the ₁-isoform of the Na⁺-K⁺ pumps is specifically regulated by activation of ß-adrenergic receptors via protein kinase A, whereas the ₂-isoform is regulated by -adrenergic receptors via protein kinase C. This raises the possibility that the lens equatorial and polar Na⁺-K⁺ pumps may be differentially regulated. If so, it may be possible to pharmacologically enhance the lens circulation as protection against some forms of cataract (see below).

Water channels.
The lens circulation model proposes that water follows the circulating Na⁺. This requires that the lens fiber and epithelial cell membranes have a significant water permeability. The most abundant membrane protein in lens fiber cells, major intrinsic protein (MIP), has strong sequence homology to members of the aquaporin family (AQP) of water channels. This relationship is further supported by structural (6) and functional similarities. When exogenously expressed in oocytes, MIP forms a water channel, but unlike channels due to many members of the AQP family, it is not sensitive to Hg²⁺ (7). Recent studies on the water permeability of membrane vesicles prepared from lens fiber cells suggest that MIP is also a major water channel in the lens (14). The water permeability of these vesicles was some 45 µm/s, was Hg²⁺ insensitive, and was dramatically reduced by the extraction of MIP from the vesicles. In contrast, lens epithelial cells had a membrane water permeability of some 135 µm/s, which was blocked by Hg²⁺. These properties are consistent with the reported expression of AQP1 in lens epithelial cells (12) and MIP in fiber cells. According to the lens circulation model, the water flowing out of each epithelial cell is due to the cumulative entry into many fiber cells; hence the water permeability of the epithelial cell membrane needs to be greater than that of the fiber cell membrane, as indeed is the case.

Isotonic transport is defined as the theoretical limiting velocity of water flow that is approached as the membrane water permeability approaches infinity and the transmembrane osmotic gradient approaches zero. On the basis of electrophysiological data reviewed in Mathias et al. (10), the Na⁺ influx across a fiber cell membrane is <0.3 x 10^–11 mol•cm^–2•s^–1. If water were to isotonically follow this solute flux, it would flow at 10^–8 cm/s. Given the above water permeability of 45 µm/s, the fiber cell transmembrane osmotic gradient necessary to generate this flow velocity is ~0.1 mosM. Thus one does indeed expect the circulation to generate a near-maximal water flow that approaches isotonic.

Glucose transporters.
Glucose is the principal metabolic fuel that the lens uses to support growth and homeostasis. Most of the glucose is processed anaerobically, with oxidative phosphorylation limited to the epithelium and newly differentiating fiber cells. The source of glucose is the aqueous humor, in which levels mirror those in the blood. Glucose uptake in the lens appears to be largely mediated by the GLUT family of facilitative glucose transport proteins (11). Although the identity of the GLUT isoforms used by the lens has long been a matter of controversy, a recent investigation at both the transcript and protein levels identified GLUT1 as the predominant isoform in the lens epithelium and GLUT3 in the fiber cells of the lens cortex (11). These results are in agreement with transport studies, which have shown that both the epithelial and the fiber cells have the capacity to transport glucose. Also, enzyme activities involved in the metabolism of glucose decrease toward the center of the lens, which is consistent with a stronger presence of glucose transporters in the cortex than in the lens core.

GLUT1 is widely expressed in vertebrate tissues in which glucose is easily accessible (13). A similar situation applies to the lens epithelium, which interfaces directly with the aqueous humor. The situation is different for the deeper-lying fiber cells. The extracellular space between the fiber cells is narrow and tortuous but sufficient for the circulating fluxes to deliver some glucose to the deeper-lying fiber cells. The finding that the epithelium is not the only site of glucose transporters and that significant levels of GLUT3 are expressed in the fiber cells is consistent with a portion of the total glucose taken up by the lens being transported via the circulation system. It is notable that GLUT3 has a lower Michaelis-Menten constant value than GLUT1 (13), thereby enabling the fiber cells to continue to take up glucose effectively, even when supplies are limited.

Summary of Na⁺-K⁺ pump activity, Na⁺ flux, water flow, and glucose transport.
A model incorporating all of the above data is summarized in Fig. 2. Na⁺ moves into fiber cells by passive electrodiffusion through an unidentified membrane channel. It is directed by the distribution of gap junctions in the outer shell of differentiating fiber cells to the equatorial surface cells, where the high concentration of Na⁺-K⁺ pumps extrudes the Na⁺. Water follows the flux of Na⁺ by entering fiber cells through channels made from MIP, and it follows the Na⁺ to the equatorial surface, where it leaves the surface cells through channels made from AQP1. The flow of water into the lens along extracellular clefts convects glucose to the inner fiber cells, where it is transported across the membrane by GLUT3. Byproducts of the anaerobic metabolism of glucose are carried back via gap junction channels to the surface, where they can be transported out of the lens.

View larger version (24K): [in this window] [in a new window]   FIGURE 2. Spatial localization of various transport proteins in the lens. In so far as they have been determined, the molecular identification and localization of the transporters and channels that mediate the lens circulation are shown. AQP, aquaporin; Cx46, 3-connexin; Cx50, 8-connexin; MIP, major intrinsic protein; GLUT, glucose transporter.

	Gap junctions play a key role in the lens circulation

Top Introduction An internal circulation... Na+, water, and glucose... Gap junctions play a... New insights into lens... Future outlook References

Fiber cells throughout the lens are connected to each other via gap junction channels composed of two related connexins, ₃ (Cx46) and ₈ (Cx50). Despite the fact that either of these connexins has the ability to form functional channels when expressed in Xenopus oocytes, inherited mutations and null mutants have shown that the presence of both is essential for the maintenance of tissue transparency. In lenses lacking the ₃-connexin, the entire core of mature fibers loses communication with the differentiating fibers and surface cells (5). Figure 3 illustrates a lens from an ₃-connexin knockout mouse. Just below the lens, the distribution of coupling conductance (in S/cm²) of cell-to-cell contact is graphed as a function of location within the lens. In lenses from the knockout mice, the conductance is reduced by ~50% in the outer differentiating fibers but falls to zero in the central mature fibers, as shown by the solid line. In contrast, in a normal lens the differentiating fiber conductance is ~1.0 S/cm² and falls to ~0.4 S/cm² in the mature fibers, as shown by the dashed line. The bottom panel shows the effect of this loss of communication on resting voltage and homeostasis of the mature fibers. As suggested by the model and indirect experimental evidence, the resting voltage of mature fibers depends on their connection to surface cells. In the lenses from ₃-connexin knockout mice, the mature fibers have a resting voltage of about –35 mV, in contrast to that in wild-type lenses of around –65 mV. Moreover, the spatial pattern of depolarization appears to reflect the spatial pattern of loss of gap junctional coupling. Lenses lacking the ₃-connexin have three distinct zones: there is the clear zone of differentiating fibers that are well coupled to surface cells by the ₈-connexin (Cx50), there is a clear zone of peripheral mature fibers that were recently differentiating fibers and therefore were coupled to surface cells but lost communication in the transition from differentiating fibers to mature fibers, and there is a central zone of mature fibers that have lost homeostasis and become cataractous. With time, the cataractous zone expands; however, the lens also continues to grow, so these three zones are maintained, although the clear mature fibers in Fig. 3 will ultimately also become cataractous. The pattern of loss of homeostasis shown in Fig. 3 is obviously consistent with the circulation being necessary for homeostasis of central fiber cells. The model prediction is that uncoupling of mature fibers cuts off the circulation from central fibers and causes a loss of homeostasis. With time, this results in formation of the central cataract.

View larger version (15K): [in this window] [in a new window]   FIGURE 3. The effect of knocking out 3-connexin (Cx46) on the mouse lens. Top: sketch of a lens lacking 3-connexin. The central zone of MF in these lenses develops a cataract, illustrated by the shaded area. The zone of DF can be functionally distinguished from MF by its relatively high coupling conductance. Middle: the coupling conductance in wild-type (dashed line) and 3-connexin knockout (solid line) lenses, graphed as a function of location in the lens. The radial distance from the lens center is r (cm) and the radius is a (cm), so r/a is the normalized radial distance from the center. In the knockout lens, the DF coupling conductance is somewhat lower than in wild type, as expected, because the 3-connexin is lost, whereas the other fiber cell 8-connexin (Cx50) is present. In lenses lacking the 3-connexin, the MF coupling conductance is zero. As a consequence, the central MF have lost homeostasis and become cataractous. Bottom: the resting voltage in wild type (dashed line) vs. 3-connexin knockout (solid line) lenses. The depolarization of MF relative to DF in the knockout lenses follows the loss of coupling, consistent with surface cells having a different electromotive potential than inner MF.

	New insights into lens cataract can be obtained from the circulation model

Top Introduction An internal circulation... Na+, water, and glucose... Gap junctions play a... New insights into lens... Future outlook References

To understand how this localized damage is generated, it is first necessary to consider the role of Cl^– fluxes in the internal circulation model. Measurements of radial differences in membrane potential and the ionic concentration of Cl^– in the whole lens have been used to calculate the electrochemical gradient for Cl^– movement as a function of radial position (10). Such an analysis predicts that Cl^– will move from the extracellular space into fiber cells deeper in the lens but will move from the cytoplasm of fiber cells to the extracellular space nearer to the lens surface (Fig. 4A). Hence one would predict that an inhibition of Cl^– channels in the inner cortex would block the uptake of Cl^– from the extracellular space by fiber cells. This would cause an accumulation of Cl^– and water in the tortuous extracellular space and the subsequent dilation of the extracellular space. Near the lens surface, the efflux of Cl^– from fiber cells would be blocked, thereby causing intracellular accumulation of osmolytes and subsequent fiber cell swelling (Fig. 4B). This agreement between predicted and observed changes in tissue architecture lends support for the proposed model of the lens microcirculation.

View larger version (24K): [in this window] [in a new window]   FIGURE 4. Modeling of Cl– movement in the lens. In the normal lens, radial differences in membrane potential of fiber cells relative to the extracellular space means that the direction of the Cl– flux changes from an influx deeper in the lens to an efflux at the lens periphery. Blockade of Cl– channels with 5-nitro-2-(3-phenylpropyamino)benzoic acid (NPPB) is expected to cause peripheral cell swelling and the dilation of extracellular space deeper in the lens. In the diabetic lens, sorbitol accumulation causes cell swelling and the activation of volume-sensitive Cl– channels. In peripheral fiber cells, an efflux of Cl– enables these cells to regulate their volume, whereas in inner fiber cells a Cl– influx exacerbates the initial cell swelling.

	Future outlook

Top Introduction An internal circulation... Na+, water, and glucose... Gap junctions play a... New insights into lens... Future outlook References

 
Assuming that the circulation is essential for homeostasis of the central fiber cells, any reduction in the circulatory system may eventually lead to cataract formation. It is possible that some reduction does occur with age, and this could lead to some forms of the senile cataract. However, it is also possible that the system can be upregulated to offset deleterious effects and avoid cataract formation. Indeed, the work on the Na⁺-K⁺ pumps (4) suggests that the circulation may be physiologically regulated. If so, then it should be possible to pharmacologically manipulate it. In this sense it is intriguing that a number of receptor isoforms (3) as well as isoforms of the Na⁺-K⁺ pumps (9) have been recently identified in the lens. Although the functional role of these receptors has yet to be determined, it is interesting to speculate that they could be used as the targets of novel therapies to prevent cataract formation by modulating the activity of the lens internal circulation.

	Acknowledgments

 
This work was supported by the Health Research Council and the Lotteries Grants Board of New Zealand and the US National Eye Institute (EY-06391).

	References

Top Introduction An internal circulation... Na+, water, and glucose... Gap junctions play a... New insights into lens... Future outlook References

 

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