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R.T. Mathias, J. Gao, II, X. Sun, T.W. White, V.N. Reddy, X. Gong, K. Varadaraj, H. Wang; Connections Between Cataracts, Calcium, Connexins and Oxidation . Invest. Ophthalmol. Vis. Sci. 2006;47(13):5419.
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© ARVO (1962-2015); The Authors (2016-present)
Glutathione peroxidase–1 (GPX–1) is a cytoplasmic enzyme that protects lens fiber cells against oxidative damage by hydrogen peroxide. GPX–1 knockout (KO) mice get an age dependent nuclear cataract, presumably due to cumulative oxidative damage to some critical proteins. We have characterized changes in ion transport, [Ca2+]i and [Na+]i that precede cataract formation in lenses from these KO mice.
Impedance studies in intact lenses were made using two intracellular microelectrodes. [Ca2+]i was measured as a function of age and position in intact lenses using an intracellular microelectrode to inject fiber cells with the Ca2+–sensitive dye Fura2. [Na+]i was similarly measured using the Na+–sensitive dye SBFI.
At 2 months of age, lenses from GPX–1 KO mice were transparent and had normal resting voltages and membrane conductances. However, outer differentiating fiber gap junction coupling conductance GDF (S/cm2) was 1.05±0.07 for Con vs 0.60±0.09 for KO; inner mature fiber coupling conductance GMF (S/cm2) was 0.42±0.03 for Con vs 0.18±0.03 for KO. This loss of coupling in KO lenses was associated with accumulation of Ca2+ and Na+ in the central MF, where [Ca2+]i (nM) was 700 for Con vs 1000 for KO and [Na+]i (mM) was 17 for Con vs 36 for KO. Lenses from older mice showed further reductions in coupling. By 14 months of age, the KO lenses had obvious opacities and [Ca2+]i was 2–3 µM in the central MF.
Lens gap junction coupling is an early target for oxidative damage. Reductions in coupling conductance interfere with the lens internal circulation and cause loss of Ca2+–homeostasis in central fiber cells. This loss may initiate proteolysis through activation Ca2+–dependent proteases and thus initiate the nuclear opacity.
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