The lens internal microcirculation system delivers solutes to the lens core faster than would be predicted by passive diffusion

Abstract

It has been proposed that optical properties of the lens are actively maintained by an internal microcirculation system that utilizes ionic and fluid fluxes to deliver nutrients to deeper regions of the lens tissue via the extracellular space, faster than would occur by passive diffusion alone. To test this hypothesis, we utilized a range of commercially available MRI reagents of varying molecular sizes that served as tracers of extracellular solute delivery. The penetration of these tracers into bovine lenses incubated in the absence and presence of solutions that inhibit the microcirculation, was monitored in real time, over a period of 4 hours, using T1-weighted MRI. We found that only the smaller contrast agents were delivered to the core of the lens and that the rate of solute penetration was significantly faster than that calculated simple diffusion. Next, the lenses were first incubated in either high extracellular K to depolarize the lens potential, or ouabain to inhibit the Na pump. These two perturbations are known to inhibit the circulating ionic and fluid fluxes that are proposed to drive solute delivery into the lens core. Both perturbations inhibited the delivery of the extracellular tracer molecules to the lens core. Our findings suggest that the microcirculation system can be potentially harnessed to deliver exogenous antioxidants to the lens core to afford mature fiber cells protection against oxidative damage that ultimately manifests as age related nuclear cataract.

Age-related changes in eye lens biomechanics, morphology, refractive index and transparency

“…Though the barrier observed in human lenses has not been reported in mouse lenses, previous reports have shown a diffusion barrier in rat lenses [84] and bovine lenses [85,86]. In bovine lenses, the barrier region is in the approximate region of fiber cell compression (relative to lens size) [85,86] that we observe in mouse lenses with advanced age. The exact structural and molecular basis for the barrier region remains unclear.…”

“…It is thought that the barrier limits antioxidant and metabolite movement into the lens and waste out of the lens leading to increased stiffness and decreased transparency with age [83]. Though the barrier observed in human lenses has not been reported in mouse lenses, previous reports have shown a diffusion barrier in rat lenses [84] and bovine lenses [85,86]. In bovine lenses, the barrier region is in the approximate region of fiber cell compression (relative to lens size) [85,86] that we observe in mouse lenses with advanced age.…”

Age‐dependent changes in glutathione metabolism pathways in the lens: New insights into therapeutic strategies to prevent cataract formation—A review

“…From here, transporters specific for GSH or glucose will uptake these substrates into the fibre cells, and in the case of glucose, supply reducing equivalents such as NADPH for GSH regeneration. In support of this model, we have shown that the microcirculation can deliver solutes to the lens nucleus faster than would be expected by passive diffusion alone, 24 and identified uptake transporters specific for GSH in the nucleus of the rat lens (unpublished data), as well as glucose transporters in the nucleus of human, bovine and rat lenses. 63 With increasing age, it is proposed that the ability of the circulation system to deliver sufficient GSH and glucose is reduced with age, and/or that the transporters in the lens nucleus are modified leading to a reduction of GSH delivery and uptake into the lens nucleus.…”

“…This fluid microcirculation convects nutrients and antioxidants via an extracellular route towards the nucleus of the lens, faster than would occur via passive diffusion alone. 24 This achieves delivery of antioxidants to the lens nucleus, which in turn, facilitates the protection of crystallin thiol groups from oxidation, effectively preventing protein aggregation and maintaining their solubility. 10,11 The accumulated fluid and associated metabolic wastes are then removed from the lens nucleus by a hydrostatic pressure gradient that drives fluid to the surface via an intercellular pathway mediated by gap junctions.…”

“…To achieve this, it has been proposed 15,21‐23 that in the absence of a blood supply, the lens operates an internal microcirculation system, which utilizes the active transport of Na + ions at the lens surface to generate a circulating flux of ions that drives an accompanying isotonic flux of fluid. This fluid microcirculation convects nutrients and antioxidants via an extracellular route towards the nucleus of the lens, faster than would occur via passive diffusion alone 24 . This achieves delivery of antioxidants to the lens nucleus, which in turn, facilitates the protection of crystallin thiol groups from oxidation, effectively preventing protein aggregation and maintaining their solubility 10,11 .…”