No abstract

This review is focused on iron metabolism in the retina and in the lens and its relation to their respective age-related pathologies, macular degeneration (AMD) and cataract (ARC). Several aspects of iron homeostasis are considered first in the retina and second in the lens, paying particular attention to the transport of iron through the blood-retinal barrier and through the lens epithelial cell barrier, to the immunochemistry of iron-related proteins and their expression in both the retina and the lens, and to the nature of the photochemical damage caused by UV light on both tissues. A comparative overview of some iron related parameters (total iron, transferrin (Tf), transferrin saturation and total iron binding capacity), in plasma and ocular tissues and fluids of three animal species is also presented. Based on results selected from the literature reviewed, and our own results, a scheme for the overall circulation of iron within and out of the eye is proposed, in which, (i) iron is pumped from the retina to the vitreous body by a ferroportin/ferroxidase-mediated process at the endfeet of Müller cells, (ii) vitreal Tf binds this iron and the complex diffuses towards the lens, (iii) the iron/Tf complex is incorporated into the lens extracellular space probably at the lens equator and moves to the epithelial-fiber interface, (iv) upon interaction with Tf receptors of the apical pole of lens epithelial cells, the iron/Tf complex is endocytosed and iron is exported as Fe(3+) by a ferroportin/ferroxidase-mediated process taking place at the basal pole of the epithelial cells, and (v) Fe(3+) is bound to aqueous humor Tf and drained with the aqueous humor into systemic blood circulation for recycling. The proposed scheme represents an example of close cooperation between the retina and the lens to maintain a constant flow of iron within the eye that provides an adequate supply of iron to ocular tissues and secures the systemic recycling of this element. It does not discount the existence of additional ways for iron to leave the eye through the blood-retinal barrier. In this review both AMD and ARC are recognized as multifactorial diseases with an important photoxidative component, and exhibiting a remarkable similitude of altered local iron metabolism. The epidemiological relationship between ARC and ferropenic anemia is explained on the basis that hepcidin, the hormone responsible for the anemia of chronic inflammation, could paradoxically cause intracellular iron overload in the lens by interfering with the proposed ferroportin/ferroxidase-mediated export of iron at the basal side of the anterior lens epithelium. Other authors have suggested that a similar situation is created in the retina in the case of AMD.

No abstract

Bityrosine was isolated from the insoluble protein of human cataractous lenses. Identification was based on correspondence with synthetic bityrosine with respect to chromatography, fluorescence, and ultraviolet and mass spectra. It is suggested that the compound may form cross-links with polypeptide chains in old and cataractous lenses, causing significant alteration in native protein structure.

Diabetes is known to affect cataract formation by means of osmotic stress induced by activated aldose reductase in the sorbitol pathway. In addition, alterations in the bioavailability of numerous extralenticular growth factors has been reported and shown to result in various consequences. We have found that the basic fibroblast growth factor (bFGF) accumulates in the vitreous humor of 3-and 8-week diabetic rats. Consequently, the associating signal transduction cascades were severely disrupted, including upregulated phosphorylation of extracellular signal-regulated kinase (ERK) and the common stress-associated mitogen-activated protein kinases p38 and SAPK/JNK. Conversely, under diabetic condition, we observed a dramatic inhibition of phosphatidylinositol-3 kinase activity in lenses obtained from the same animal. Rats treated with the aldose reductase inhibitor AL01576 for the duration of the diabetic condition showed that the diabetes-induced lenticular signaling alterations were normalized, comparable to controls. However, treatment of AL01576 in vitro was ineffective at normalizing the altered constituents in extracted diabetic vitreous after the onset of diabetes. The effect of AL01576 in the high galactoseinduced cataract model in vitro was also examined. Administration of AL01576 to lens organ culture normalized the aberrant signaling effects and morphological characteristics associated with in vitro sugar cataract formation. In conclusion, our findings demonstrate diabetes-associated alterations in the lens signal transduction parameters and the effectiveness of AL01576 at normalizing such alterations. The causes for these alterations can be attributed to elevated vitreal bFGF in conjunction with osmotic stress and associated attenuation in redox status of the lens.