In the mammalian lens, the concentration of ions inside the cells plays a major role in the development of cataract. Ions such as Ca2+ have been shown to form aggregates with lens a-crystallins, thereby causing opacity (Benedek, 1971; Benedek et al., 1999). Low intracellular calcium is maintained by Na + /Ca2+ exchanger and Ca2+-ATPase (Hightower et al, 1980). Evidence exists for the presence of Na + /Ca2+ exchanger in the apical membrane of lens epithelial cells (Ye and Zadunaisky, 1992a,b). In rabbit, bovine, dog, and rat lenses, while the lack of sodium did not affect the efflux of Ca2+ from the cells, inhibitors of Ca2 + -ATPase, lanthanum and propranolol inhibited Ca2+ efflux (Hightower et al, 1980). ATPase is present in both the lens epithelium and cortex but absent in the nucleus, with the expression being the highest in the epithelium (Ye and Zadunaisky, 1992b) (Fig. 8). Na + /H+ exchanger regulates intracellular pH in the lens epithelial cells as well as the lens fiber cells (Wolosin et al., 1988).
Because of lens avascularity, there is a need for the continuous supply of nutrients such as glucose, amino acids, and ascorbic acid for metabolic and synthetic reactions. Lens derives most of its nutrients from aqueous humor. Entry of solutes into the lens occurs by both saturable and nonsa-
turable paths (Merrimann-Smith et al., 1999). While water, chloride, urea, and glycerol are likely to traverse the plasma membrane of the lens epithelial cells by simple diffusion, amino acids are transported actively. The uptake of D-glucose and nonmetabolizable 3-O-methyl-D-glucose into the rat lens was saturable and the capacity of the system for D-glucose was similar at both anterior and posterior surfaces. Transport studies with a variety of sugars indicated that a C-1 conformation and the presence of H or OH on carbon number 1 are critical to transport. Furthermore, the GLUT family of proteins, GLUT 1 and GLUT3, is predominantly responsible for the uptake of glucose in the anterior epithelium (Kern and Ho, 1973; Merrimann-Smith et al., 1999). These transporters are abundant in the lens nucleus and present in the cortex to a lower extent in both human and rat eyes.
Lens contains a higher concentration of amino acids compared to the surrounding aqueous and vitreous humors. In vitro lens uptake studies with labeled amino acids indicated saturation kinetics, energy and temperature dependency, consistent with their active transport (Zlokovic et al., 1992). Furthermore, separate systems exist for the transport of neutral, basic, and acidic amino acids in the lens. Lens expresses A-, L-, Gly-, and Ly + -systems (Kern et al., 1977). The ASC system, selective for three- or four-carbon neutral amino acids, is present in the lens epithelial cell, and it is the preferred pathway at physiological levels of L-alanine, L-serine, and L-cystein (Kern et al., 1977). The lens behaves like a "pump-leak system'' in which the substances actively transported by the epithelium are concentrated in the lens and then diffuse toward the posterior pole and eventually leave the lens across the posterior capsule.
The rate of differentiation of lens epithelial cells into fiber cells is dependent on the synthesis of phosphoinositides from myoinositol (Zelenka and Vu, 1984). Since myoinositol synthesis in the lens is negligible, membrane transport is the major source of cellular myoinositol. The lens allows both sodium-dependent active transport and passive diffusional transport of myo-inositol (Diecke et al., 1995).
The oxidative balance in the lens is maintained by ascorbic acid, whose primary source is aqueous humor (Kern and Zolot, 1987). The active uptake of ascorbic acid by lens epithelium is 20 times greater than L-glucose. Within 7 minutes following systemic administration, [14C]ascorbic acid is concentrated more in the lens epithelium than the aqueous humor.
Nucleotides enter the lens via Na + -dependent transport processes, with the uptake being comparable at the two surfaces of the lens, similar to sugars (Redzic et al., 1998). Saturable uptake was observed for purines such as guanosine, inosine, and adenosine, but not for pyrimidines and adenine.
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