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Oxidative stress, lens gap junctions, and cataracts.

ABSTRACT: The eye lens is constantly subjected to oxidative stress from radiation and other sources. The lens has several mechanisms to protect its components from oxidative stress and to maintain its redox state, including enzymatic pathways and high concentrations of ascorbate and reduced glutathione. With aging, accumulation of oxidized lens components and decreased efficiency of repair mechanisms can contribute to the development of lens opacities or cataracts. Maintenance of transparency and homeostasis of the avascular lens depend on an extensive network of gap junctions. Communication through gap junction channels allows intercellular passage of molecules (up to 1 kDa) including antioxidants. Lens gap junctions and their constituent proteins, connexins (Cx43, Cx46, and Cx50), are also subject to the effects of oxidative stress. These observations suggest that oxidative stress-induced damage to connexins (and consequent altered intercellular communication) may contribute to cataract formation.

SUBMITTER: Berthoud VM

PROVIDER: S-EPMC2763361 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Oxidative stress, lens gap junctions, and cataracts.

Berthoud Viviana M VM Beyer Eric C EC

Antioxidants & redox signaling 20090201 2

The eye lens is constantly subjected to oxidative stress from radiation and other sources. The lens has several mechanisms to protect its components from oxidative stress and to maintain its redox state, including enzymatic pathways and high concentrations of ascorbate and reduced glutathione. With aging, accumulation of oxidized lens components and decreased efficiency of repair mechanisms can contribute to the development of lens opacities or cataracts. Maintenance of transparency and homeosta ...[more]

PMID: 18831679

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Project description:BackgroundThe eye is well known to be sensitive to clearly high doses (>2 Gy) of ionizing radiation. In recent years, however, cataracts have been observed in populations exposed to lower doses. Interventional cardiologists are repeatedly and acutely exposed to scattered ionizing radiation (X-rays) during the diagnostic and therapeutic procedures they perform. These "low" exposures may cause damage to the lens of the eye and induce early cataracts, known as radiation-induced cataracts. The O'CLOC study (Occupational Cataracts and Lens Opacities in interventional Cardiology) was designed to test the hypothesis that interventional cardiologists, compared with an unexposed reference group of non-interventional cardiologists, have an increased risk of cataracts.Method/designThe O'CLOC study is a cross-sectional study that will include a total of 300 cardiologists aged at least 40 years: one group of exposed interventional cardiologists and another of non-interventional cardiologists. The groups will be matched for age and sex. Individual information, including risk factors for cataracts (age, diabetes, myopia, etc.), will be collected during a telephone interview. A specific section of the questionnaire for the exposed group focuses on occupational history, including a description of the procedures (type, frequency, radiation protection tool) used. These data will be used to classify subjects into "exposure level" groups according to cumulative dose estimates. Eye examinations for all participants will be performed to detect cataracts, even in the early stages (lens opacities, according to LOCS III, the international standard classification). The analysis will provide an estimation of the cataract risk in interventional cardiology compared with the unexposed reference group, while taking other risk factors into account. An analysis comparing the risks according to level of exposure is also planned.DiscussionThis epidemiological study will provide further evidence about the potential risk of radiation-induced cataracts at low doses and contribute to cardiologists' awareness of the importance of radiation protection.Trial registrationNCT01061463.

Project description:Failure to control oxidative stress is closely related to aging and to a diverse range of human diseases. We have reported that protein kinase C gamma (PKCgamma) acts as a primary oxidative stress sensor in the lens. PKCgamma has a Zn-finger C1B stress switch domain, residues 101-150. Mutation, H101Y, in the C1B domain of PKCgamma proteins causes a failure of the PKCgamma oxidative stress response [Lin, D., Takemoto, D.J., 2005. Oxidative activation of protein kinase Cgamma through the C1 domain. Effects on gap junctions. J. Biol. Chem. 280, 13682-13693]. Some human neurodegenerative spinocerebellar ataxia type 14 are caused by mutations in the PKCgamma C1B domain. In the current study we have investigated the effects of these mutations on lens epithelial cell responses to oxidative stress. The results demonstrate that PKCgamma C1B mutants had lower basal enzyme activities and were not activated by H(2)O(2). Furthermore, the PKCgamma mutations caused a failure of endogenous wild type PKCgamma to be activated by H(2)O(2). These PKCgamma mutations abolished the effect of H(2)O(2) on phosphorylation of Cx43 and Cx50 by H(2)O(2) activation of PKCgamma. The cells with PKCgamma C1B mutations had more Cx43 and/or Cx50 gap junction plaques which were not decreased by H(2)O(2). Since open gap junctions could have a bystander effect this could cause apoptosis to occur. H(2)O(2) (100 microM, 3 h) activated a caspase-3 apoptotic pathway in the lens epithelial cells but was more severe in cells expressing PKCgamma mutations. The presence of 18alpha-glycyrrhetinic acid (AGA), an inhibitor of gap junctions, decreased Cx43 and Cx50 protein levels and gap junction plaque number. This reduction in gap junctions by AGA resulted in inhibition of H(2)O(2)-induced apoptosis. Our results demonstrate that there is a dominant negative effect of PKCgamma C1B mutations on endogenous PKCgamma which results in loss of control of gap junctions. Modeled structures suggest that the severity of C1B mutation effects may be related to the extent of loss of C1B structure. Mutations in the C1B domain of PKCgamma result in increased apoptosis in lens epithelial cells. This can be prevented by a gap junction inhibitor. Thus, propagation of apoptosis from cell-to-cell in lens epithelial cells may be through open gap junctions. The control of gap junctions requires PKCgamma.

Dataset Information

Oxidative stress, lens gap junctions, and cataracts.

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Oxidative stress, lens gap junctions, and cataracts.

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