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Enhanced diabetes-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 Clinical Sciences, Ophthalmology.
2009 (English)In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, Vol. 50, no 6, 2913-2918 p.Article in journal (Refereed) Published
Abstract [en]

PURPOSE: Oxidative stress is thought to contribute to diabetes-induced cataract, and the authors have previously demonstrated that lenses from mice lacking the antioxidant enzyme copper-zinc superoxide dismutase (SOD1) show elevated levels of superoxide radicals and are more prone in vitro to develop glucose-induced cataract than are wild-type lenses. In the present study the effect of streptozotocin-induced diabetes mellitus on cataract formation in SOD1-null and wild-type mice in vivo was examined.

METHODS: Eight weeks after diabetes was established by repeated intraperitoneal streptozotocin injections, the mice were killed and the lenses removed and photographed in retroillumination. The cataract was quantified from the photographs by digital image analysis and the lens contents of glutathione (GSH) as well as the lens protein carbonyl contents suggestive of protein oxidation were analyzed.

RESULTS: The streptozotocin-induced diabetic SOD1-null mice developed more cataract than the diabetic wild-type mice. Also, lens GSH levels were lower in the diabetic SOD1-null mice than in the nondiabetic SOD1-null mice. However, the protein carbonyls were equally raised in the diabetic mice of both genotypes.

CONCLUSIONS: The increased cataract formation and the compromised antioxidant capacity found in the diabetic SOD1-null lenses thus emphasize the involvement of superoxide radicals in diabetes-induced cataract.

Place, publisher, year, edition, pages
2009. Vol. 50, no 6, 2913-2918 p.
Keyword [en]
glucose-induced cataract; oxidative stress; nitric-oxide; in-vitro; protein oxidation; lens; mouse; model; establishment; mechanism
National Category
Research subject
URN: urn:nbn:se:umu:diva-23802DOI: 10.1167/iovs.09-3510PubMedID: 19324844OAI: diva2:225707
Available from: 2009-06-29 Created: 2009-06-29 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
National Category
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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