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Venkat N. Reddy, Frank J. Giblin, Li-Ren Lin, Loan Dang, Nalin J. Unakar, David C. Musch, Daniel L. Boyle, Larry J. Takemoto, Ye-Shih Ho, Tina Knoernschild, Anselm Juenemann, Elke Lütjen–Drecoll; Glutathione Peroxidase-1 Deficiency Leads to Increased Nuclear Light Scattering, Membrane Damage, and Cataract Formation in Gene-Knockout Mice. Invest. Ophthalmol. Vis. Sci. 2001;42(13):3247-3255.
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purpose. Previous in vitro studies with transgenic and gene-knockout mice have
shown that lenses with elevated levels of glutathione peroxidase
(GPX)-1 activity are able to resist the cytotoxic effect of
H2O2, compared with normal lenses and lenses
from GPX-1–deficient animals. The purpose of this study was to
investigate the functional role of this enzyme in antioxidant
mechanisms of lens in vivo by comparing lens changes of gene-knockout
mice with age-matched control animals.
methods. In vivo lens changes were monitored by slit lamp biomicroscopy, and
enucleated lenses were examined under a stereomicroscope in
gene-knockout animals and age-matched control animals ranging in age
from 3 weeks to 18 months. Transmission (TEM) and confocal microscopy
were performed on different regions of lenses after the mice were
killed at various times.
results. Slit lamp images showed an increase in nuclear light scattering (NLS)
in gene-knockout mice compared with control animals. TEM revealed
changes in the nucleus as early as 3 weeks of age by the appearance of
waviness of fiber membranes. With increasing age, there was greater
distortion of fiber membranes and distension of interfiber space at the
apex of fiber cells compared with control mice. The changes in nuclear
fiber membranes were even more dramatic, as observed by confocal
microscopy, which was performed on thicker sections. In contrast to the
changes in the lens nucleus, the morphology of the epithelium and
superficial cortex remained unchanged in knockout animals during the
same experimental period, consistent with slit lamp observations.
Stereomicroscopy of ex vivo lenses demonstrated a significant increase
in opacification in gene-knockout mice relative to control animals of
the same age. This effect became evident in mice aged 5 to 9.9 months
and persisted thereafter in older animals, resulting in mature
cataracts after 15 months.
conclusions. The results demonstrate the critical role of GPX-1 in antioxidant
defense mechanisms of the lens nucleus. The increased NLS appears to be
associated with damage to fiber membranes in the nucleus, which is
particularly susceptible to oxidative challenge because of the
deficiency of GPX-1. It is suggested that the lens membrane changes in
the knockout animals may be due to the formation of lipid peroxides,
which serve as substrates for GPX-1. Cataract development in
gene-knockout mice appeared to progress from focal opacities, apparent
at an earlier age, to lamellar cataracts between 6 and 10 months, and
finally to complete opacification in animals older than 15 months. This
is the first reported phenotype in GPX-1–knockout
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