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In vitro glucose-induced cataract in copper-zinc superoxide dismutase null mice
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
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2005 (English)In: Experimental Eye Research, ISSN 0014-4835, E-ISSN 1096-0007, Vol. 81, no 6, 639-646 p.Article in journal (Refereed) Published
Abstract [en]

The purpose of this study was to evaluate the involvement of the superoxide radical in glucose-induced cataract using lenses from mice lacking the cytosolic copper-zinc superoxide dismutase (SOD1). Lenses from wild-type mice and SOD1 null mice were kept in organ culture with either 5.6 or 55.6 mM glucose for 6 days. The cataract formation was followed with digital image analysis and ocular staging. The lens damage was further quantified by analysis of the leakage of lactate dehydrogenase into the medium by the uptake of 86Rb and by determining the water content of the lenses. The formation of superoxide radicals in the lenses was assessed with lucigenin-derived chemiluminescence. Immunohistochemical staining for SOD1 was also performed on murine lenses. The SOD1 null lenses exposed to high glucose developed more cataract showed an increased leakage of lactate dehydrogenase and developed more oedema compared to the control lenses. At 5.6 mM glucose there was no difference between the SOD1 null and wild-type lenses. Staining for SOD1 was seen primarily in the cortex of the wild-type lens. This in vitro model suggests an involvement of the superoxide radical and a protective effect of SOD1 in glucose-induced cataract formation.

Place, publisher, year, edition, pages
2005. Vol. 81, no 6, 639-646 p.
Keyword [en]
animals, cataract/chemically induced/enzymology, female, glucose/pharmacology, image processing, computer-assisted, lens; crystalline/drug effects, male, mice, mice, knockout, organ culture techniques, superoxide dismutase/deficiency/genetics/physiology
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URN: urn:nbn:se:umu:diva-15229DOI: 10.1016/j.exer.2005.03.022PubMedID: 15949797Local ID: 744OAI: diva2:154901
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2012-09-22Bibliographically approved
In thesis
1. Superoxide dismutase 1 and cataract
Open this publication in new window or tab >>Superoxide dismutase 1 and cataract
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Light and oxygen generate harmful reactive oxygen species (ROS) in the lens, causing biochemical changes that gradually disarrange the lens fibres resulting in light scattering and loss of transparency. In the healthy eye, this chronic exposure to oxidative stress may lead to age-related cataract. However, there are also some conditions that accelerate cataract formation, such as diabetes mellitus, in which increased glucose levels may contribute to increased generation of ROS.

The superoxide dismutases (SOD) participate in the defence against ROS by catalysing the dismutation of superoxide radicals. The main SOD isoenzyme in the lens is copper-zinc superoxide dismutase (SOD1). The aim of this thesis was to explore if this antioxidant enzyme is important for the protection against age-related and diabetes-induced cataract development.

Lenses from wild-type mice and mice lacking SOD1 were incubated in high levels of glucose in vitro and their transparency and damage evaluated daily. Also, the impact of nitric oxide was studied by adding a nitric oxide synthase inhibitor. Furthermore, in vivo cataract formation in relation to the oxidative status of the lens was evaluated in streptozotocin-induced diabetic mice as well as in non-diabetic mice of both genotypes. Finally, the spontaneous age-related cataract development was studied in both genotypes.

In vitro, the SOD1 null lenses showed increased levels of superoxide radicals and developed dense nuclear lens opacities upon exposure to high levels of glucose. They also showed increased lens leakage of lactate dehydrogenase, reduced transport function across cell membranes, and increased water contents. However, the lens damage and cataract formation were eliminated when the synthesis of nitric oxide was inhibited. This indicates that both superoxide and nitric oxide have important roles in glucose-induced cataract development possibly through their reaction with each other which generates the highly reactive peroxynitrite.

In vivo, both the SOD1 null and the wild-type mice showed cortical cataract changes after 8 weeks of diabetes, although the SOD1 null mice showed a more pronounced cataract formation than the wild-type mice in relation to the level of hyperglycaemia. As cataract formation was accentuated the lenses showed diminishing levels of glutathione but increasing amounts of protein carbonyls, suggesting a reduced lens antioxidant capacity as well as increased lens protein oxidation. Non-diabetic young (18 weeks of age) SOD1 null mice did not show any signs of cataract. At 1 year of age they had developed some cortical lens obscurity as compared to the wild-type mice which did not show equivalent changes until 2 years of age.

The results presented in this thesis show that SOD1 null mice are more prone to develop diabetes-induced and age-related cataract than wild-type mice. The findings thus further endorse the importance of oxidative stress as a contributor to cataract development and indicate that both superoxide and nitric oxide may be damaging to the lens. I therefore conclude that the antioxidant enzyme SOD1 is important for the protection against cataract.

Place, publisher, year, edition, pages
Umeå: Institutionen för klinisk vetenskap, 2009. 76 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1254
cataract, diabetes mellitus, nitric oxide, superoxide, superoxide dismutase, SOD1 null mice
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Research subject
urn:nbn:se:umu:diva-21032 (URN)978-91-7264-749-7 (ISBN)
Oftalmiatrik, 901 87, Umeå
Public defence
2009-04-24, Betula, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Available from: 2009-04-06 Created: 2009-04-01 Last updated: 2012-05-03Bibliographically approved

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Olofsson, Eva MMarklund, Stefan LKarlsson, KurtBrännström, ThomasBehndig, Anders
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