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Superoxide dismutase 1 and cataract
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
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.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1254
Keyword [en]
cataract, diabetes mellitus, nitric oxide, superoxide, superoxide dismutase, SOD1 null mice
National Category
Ophthalmology
Research subject
Ophtalmology
Identifiers
URN: urn:nbn:se:umu:diva-21032ISBN: 978-91-7264-749-7 (print)OAI: oai:DiVA.org:umu-21032DiVA: diva2:210411
Distributor:
Oftalmiatrik, 901 87, Umeå
Public defence
2009-04-24, Betula, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2009-04-06 Created: 2009-04-01 Last updated: 2012-05-03Bibliographically approved
List of papers
1. In vitro glucose-induced cataract in copper-zinc superoxide dismutase null mice
Open this publication in new window or tab >>In vitro glucose-induced cataract in copper-zinc superoxide dismutase null mice
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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.

Keyword
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
National Category
Ophthalmology
Identifiers
urn:nbn:se:umu:diva-15229 (URN)10.1016/j.exer.2005.03.022 (DOI)15949797 (PubMedID)744 (Local ID)744 (Archive number)744 (OAI)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2012-09-22Bibliographically approved
2. Glucose-induced cataract in CuZn-SOD null lenses: an effect of nitric oxide?
Open this publication in new window or tab >>Glucose-induced cataract in CuZn-SOD null lenses: an effect of nitric oxide?
2007 (English)In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 42, no 7, 1098-1105 p.Article in journal (Refereed) Published
Abstract [en]

Lenses from mice lacking the antioxidant enzyme copper-zinc superoxide dismutase (SOD1) show elevated levels of superoxide radicals and are prone to developing cataract when exposed to high levels of glucose in vitro. As superoxide may react further with nitric oxide, generating cytotoxic reactive nitrogen species, we attempted to evaluate the involvement of nitric oxide in glucose-induced cataract. Lenses from SOD1-null and wild-type mice were incubated with high or normal levels of glucose (55.6 and 5.56 mM). A nitric oxide synthase inhibitor (L-NAME) or a nitric oxide donor (DETA/NO) was added to the culture medium. Cataract development was assessed using digital image analysis of lens photographs and cell damage by analyzing the leakage of lactate dehydrogenase. The levels of superoxide radicals in the lenses were also measured. L-NAME was found to reduce cataract development and cell damage in the SOD1-null lenses exposed to high glucose. On the other hand, DETA/NO accelerated cataract development, especially in the SOD1-null lenses. These lenses also showed a higher leakage of lactate dehydrogenase than wild-type controls. We conclude that a combination of high glucose and absence of SOD1 increases the formation of cataract and that nitric oxide probably contributes to this process.

Keyword
animals, cataract/chemically induced, culture media, enzyme inhibitors/pharmacology, glucose/adverse effects, lens/crystalline/metabolism/pathology, luminescence, mice, mice/knockout, NG-nitroarginine methyl ester/pharmacology, nitric oxide/physiology, nitric oxide synthase/antagonists & inhibitors/metabolism, superoxide dismutase/genetics/metabolism
National Category
Ophthalmology
Identifiers
urn:nbn:se:umu:diva-7585 (URN)10.1016/j.freeradbiomed.2007.01.012 (DOI)17349936 (PubMedID)744 (Local ID)744 (Archive number)744 (OAI)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2012-09-22Bibliographically approved
3. Enhanced diabetes-induced cataract in copper-zinc superoxide dismutase-null mice
Open this publication in new window or tab >>Enhanced diabetes-induced cataract in copper-zinc superoxide dismutase-null mice
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.

Keyword
glucose-induced cataract; oxidative stress; nitric-oxide; in-vitro; protein oxidation; lens; mouse; model; establishment; mechanism
National Category
Ophthalmology
Research subject
Medicine
Identifiers
urn:nbn:se:umu:diva-23802 (URN)10.1167/iovs.09-3510 (DOI)19324844 (PubMedID)
Available from: 2009-06-29 Created: 2009-06-29 Last updated: 2012-09-22Bibliographically approved
4. Enhanced age-related cataract in copper-zinc superoxide dismutase null mice
Open this publication in new window or tab >>Enhanced age-related cataract in copper-zinc superoxide dismutase null mice
2012 (English)In: Clinical and Experimental Ophthalmology, ISSN 1442-6404, E-ISSN 1442-9071, Vol. 40, no 8, 813-820 p.Article in journal (Refereed) Published
Abstract [en]

Background: As the lens is constantly exposed to light and oxygen that generate harmful reactive oxygen species, the importance of the intracellular antioxidant enzyme copper-zinc superoxide dismutase for the protection against age-related cataract development was explored.

Methods: The development of lens opacities and the lens oxidative status were studied in different age groups of mice lacking copper-zinc superoxide dismutase and in wild-type mice. The lens opacities were quantified from lens photographs using digital image analysis. Thereafter, the lenses were homogenized and analysed regarding their contents of reduced glutathione and protein carbonyls suggestive of protein oxidation.

Results: The 18-week-old mice of both genotypes had clear lenses. At 1 year of age, the copper-zinc superoxide dismutase null mice had developed cortical lens opacities, whereas the wild-type mice did not show equivalent changes until 2 years of age. The lens contents of glutathione decreased only in the 2-year-old wild-type mice, whereas the carbonyls increased over time without any differences between the two genotypes.

Conclusions: This study indicates that the lack of copper-zinc superoxide dismutase may accelerate age-related lens opacity development and that intracellular superoxide-derived oxidative stress may be damaging to the lens during ageing. Participation of the anti-oxidant enzyme copper-zinc superoxide dismutase in the protection against age-related cataract was thus suggested.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2012
National Category
Ophthalmology
Research subject
Ophtalmology
Identifiers
urn:nbn:se:umu:diva-21028 (URN)10.1111/j.1442-9071.2012.02794.x (DOI)
Available from: 2009-04-01 Created: 2009-04-01 Last updated: 2013-11-26Bibliographically approved

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