Diabetes mellitus is recognized as a leading cause of new cases of blindness among Americans between the ages of 20 and 74. Aldose reductase (AR) has been implicated in the pathogenesis of diabetic cataract and retinopathy, but we do not understand the mechanism. Diabetes causes activation of kinase signaling molecules, which stimulate production of proinflammatory molecules. AR inhibitors prevent kinase activation and suppress inflammation. Prevention of inflammation is also provided by a group of proteins called the perixosome proliferator-activated receptors (PPAR). Drugs that activate the PPAR family protect against inflammation in the diabetic retina, much like AR inhibitors. The similar benefits of AR inhibitors and PPAR agonists against diabetic retinopathy and inflammation suggest they could be operating through a common pathway. However, there is a gap in our understanding of this process. We have developed a series of mouse models to evaluate the role of AR in diabetic eye disease. We found that elevated AR expression causes activation of kinases, which leads to cell proliferation and cataracts. Evidence suggests that activated AR may lead to inflammation and suppress pathways involved in PPAR signaling. We propose a series of three specific aims to investigate a role for AR in diabetic eye disease.
In aim 1, we will test the hypothesis that activation of AR leads to imbalances in lens epithelial cell (LEC) proliferation and differentiation. We will examine kinases and differentiation markers to investigate why activation of AR causes hyperproliferation of lens epithelial cells. DNA microarray experiments will be conducted to determine if AR activation leads to up- or down-regulation of gene clusters. Cell cycle analysis will be carried out to determine if AR activation alters mechanisms of cell cycle control.
In aim 2, we will test the hypothesis that AR activation contributes to diabetic eye disease through modulation of signaling pathways. We will evaluate the consequences of AR-mediated kinase activation on the degenerative lens phenotype in our transgenic model.
In aim 3, we will test the hypothesis that AR-mediated PPAR inhibition contributes to diabetic eye disease using mice with disabled genes for AR and/or PPAR. Our long term objectives are to elucidate mechanisms involved in diabetic eye disease in order to develop strategies to prevent or delay the devastating effects of diabetes on the eye.

Public Health Relevance

Diabetes mellitus is a leading cause of new cases of blindness among Americans between the ages of 20 and 74. The proposed research seeks to elucidate mechanisms behind diabetic eye disease so that strategies can be developed for development of new drugs and therapies to prevent vision loss.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY005856-29
Application #
8447037
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Araj, Houmam H
Project Start
1988-07-16
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
29
Fiscal Year
2013
Total Cost
$430,021
Indirect Cost
$148,962
Name
University of Colorado Denver
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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Chang, Kun-Che; Shieh, Biehuoy; Petrash, J Mark (2016) Aldose reductase mediates retinal microglia activation. Biochem Biophys Res Commun 473:565-71
Chang, Kun-Che; Petrash, J Mark (2015) Aldose Reductase Mediates Transforming Growth Factor β2 (TGF-β2)-Induced Migration and Epithelial-To-Mesenchymal Transition of Lens-Derived Epithelial Cells. Invest Ophthalmol Vis Sci 56:4198-210
Snow, Anson; Shieh, Biehuoy; Chang, Kun-Che et al. (2015) Aldose reductase expression as a risk factor for cataract. Chem Biol Interact 234:247-53
Chang, Kun-Che; Snow, Anson; LaBarbera, Daniel V et al. (2015) Aldose reductase inhibition alleviates hyperglycemic effects on human retinal pigment epithelial cells. Chem Biol Interact 234:254-60
Lee, Chieh Allen; Li, Guangyuan; Patel, Mansi D et al. (2014) Diabetes-induced impairment in visual function in mice: contributions of p38 MAPK, rage, leukocytes, and aldose reductase. Invest Ophthalmol Vis Sci 55:2904-10
Li, Linfeng; Chang, Kun-Che; Zhou, Yaming et al. (2014) Design of an amide N-glycoside derivative of β-glucogallin: a stable, potent, and specific inhibitor of aldose reductase. J Med Chem 57:71-7
Chang, Kun-Che; Ponder, Jessica; Labarbera, Daniel V et al. (2014) Aldose reductase inhibition prevents endotoxin-induced inflammatory responses in retinal microglia. Invest Ophthalmol Vis Sci 55:2853-61
Chang, Kun-Che; Laffin, Brian; Ponder, Jessica et al. (2013) Beta-glucogallin reduces the expression of lipopolysaccharide-induced inflammatory markers by inhibition of aldose reductase in murine macrophages and ocular tissues. Chem Biol Interact 202:283-7
Tang, Jie; Du, Yunpeng; Petrash, J Mark et al. (2013) Deletion of aldose reductase from mice inhibits diabetes-induced retinal capillary degeneration and superoxide generation. PLoS One 8:e62081

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