Reply to: A Critical Appraisal of the Lens Circulation Model—An Experimental Paradigm for Understanding the Maintenance of Lens Transparency?

Abstract

The authors of the Point article clearly describe the fluid circulation model (FCM) in its current form. The two articles present contrasting views of lens physiology. In the view of Donaldson et al., mature fiber cells in the adult lens are metabolically active, requiring a steady supply of substrates and removal of metabolic end products. If this view were correct, robust circulation of intracellular fluid might be needed. Our perspective, which is supported by several published studies not considered by proponents of the FCM, is that mature fiber cells have little or no metabolic activity. They depend on superficial fiber cells to maintain their ionic balance and to preserve a reducing environment in their cytoplasm. The movement of ions and reducing agents such as glutathione (GSH) to and from the lens core occurs by simple diffusion across the gap junctions of mature fiber cells, not by an internal circulatory system. The data we present suggest that the FCM is unlikely to be valid. To test whether the FCM is an accurate view of lens physiology, it should be sufficient to perform only two experiments. One would be to repeat the study cited in Figure 1 of our Counterpoint article on adult lenses, while monitoring extralenticular currents. Displacement of a gap-junction–permeable dye, relative to an impermeant marker, would directly measure fluid flow in the intact lens, if it exists. The second experiment should test whether homogenates of adult human nuclear fiber cells transform a substantial amount of labeled glucose into pyruvate and amino acid precursors into reduced glutathione. The first directly measures flow in the lens, and the second tests whether GSH can be synthesized and reduced in mature fiber cells. Figure 4 of our Counterpoint article shows that unidirectional flow from the center to the periphery of the lens would impede the diffusion of small molecules such as GSH, in the opposite direction. Therefore, the FCM requires that sufficient metabolism persist in the nucleus to generate ATP from glucose and reduced glutathione from amino acids and NADPH. For this reason, flow and metabolism are inextricably linked. If flow cannot be demonstrated or GSH cannot be synthesized and reduced by local metabolism in the lens nucleus, the FCM hypothesis is untenable.