The polyol pathway enzyme aldose reductase (AR) has been implicated in several pleiotrophic complications of diabetes. In animal models, AR inhibitors (ARI) prevent or delay multiple diabetic complications. However, the clinical efficacy of ARI remains uncertain, and the physiological role of AR is unclear. Our results during the past funding period show that hydrophobic aldehydes, such as those derived from lipid peroxidation are reduced more efficiently by AR than is glucose; raising the possibility that AR normally participates in the detoxification of lipid-derived aldehydes, and in diminishing oxidative stress. Our central hypothesis is that by altering the cellular redox state, and inducing post-transnational modifications, prolonged diabetes perturbs the antioxidant role of AR, so that it contributes to, rather than combats, the oxidative effects of high glucose. To test this hypothesis, we will investigate the post-translational changes in AR under hyperglycemic vs. normoglycemic conditions in human lens epithelial cells (HLEC), vascular smooth muscle cells (VSMC) and vascular endothelial cells (VEC). Based on our results showing that AR could be nitrosated or glutathiolated in vitro, we will determine how an increase in nitric oxide (NO) synthesis, nitrosothiols, and NO donors affects cellular AR activity (Aim 1). By electrospray mass spectroscopy of immunoprecipitates, we will identify covalent changes in AR in cells or tissues exposed to hyperglycemia or diabetes (Aim 2). The role of AR in regulating endogenous oxidative stress will be examined within the context of tumor necrosis factor-alpha (TNF-alpha)-induced signaling, which is increased in diabetes and is mediated by reactive oxygen species. We will test whether inhibition of AR prevents the activation of NF-kappaB by TNF-alpha and so leads to a decrease in TNFalpha-induced VSMC growth and HLEC or VEC apoptosis (Aim 3). We will examine whether the basal activation of NF-KappaB by high glucose is prevented by ARI, and whether they prevent the mitogenic and apoptotic effects of TNF-alpha in high glucose (Aim 4). These studies should lead to the identification of a novel mechanism by which ARI prevents diabetic complications, and will provide a better understanding to the regulation and the role of AR in normoglycemic conditions. Our investigations will also help in evaluating the long-term risks or benefits of anti-AR therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37DK036118-15
Application #
6572470
Study Section
Visual Sciences A Study Section (VISA)
Program Officer
Jones, Teresa L Z
Project Start
1987-04-01
Project End
2008-05-31
Budget Start
2003-07-01
Budget End
2004-05-31
Support Year
15
Fiscal Year
2003
Total Cost
$350,150
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Shoeb, Mohammad; Ansari, Naseem H; Srivastava, Satish K et al. (2014) 4-Hydroxynonenal in the pathogenesis and progression of human diseases. Curr Med Chem 21:230-7
Shoeb, Mohammad; Ramana, Kota V; Srivastava, Satish K (2013) Aldose reductase inhibition enhances TRAIL-induced human colon cancer cell apoptosis through AKT/FOXO3a-dependent upregulation of death receptors. Free Radic Biol Med 63:280-90
Saxena, Ashish; Tammali, Ravinder; Ramana, Kota V et al. (2013) Aldose Reductase Inhibition Prevents Colon Cancer Growth by Restoring Phosphatase and Tensin Homolog Through Modulation of miR-21 and FOXO3a. Antioxid Redox Signal 18:1249-62
Yadav, Umesh C S; Ramana, K V; Srivastava, Satish K (2013) Aldose reductase regulates acrolein-induced cytotoxicity in human small airway epithelial cells. Free Radic Biol Med 65:15-25
Yadav, Umesh C S; Srivastava, Satish K; Ramana, Kota V (2012) Prevention of VEGF-induced growth and tube formation in human retinal endothelial cells by aldose reductase inhibition. J Diabetes Complications 26:369-77
Kalariya, Nilesh M; Shoeb, Mohammad; Ansari, Naseem H et al. (2012) Antidiabetic drug metformin suppresses endotoxin-induced uveitis in rats. Invest Ophthalmol Vis Sci 53:3431-40
Pandey, Saumya; Srivastava, Satish K; Ramana, Kota V (2012) A potential therapeutic role for aldose reductase inhibitors in the treatment of endotoxin-related inflammatory diseases. Expert Opin Investig Drugs 21:329-39
Srivastava, Satish K; Yadav, Umesh C S; Reddy, Aramati B M et al. (2011) Aldose reductase inhibition suppresses oxidative stress-induced inflammatory disorders. Chem Biol Interact 191:330-8
Reddy, Aramati B M; Tammali, Ravinder; Mishra, Rakesh et al. (2011) Aldose reductase deficiency protects sugar-induced lens opacification in rats. Chem Biol Interact 191:346-50
Tammali, Ravinder; Reddy, Aramati B M; Saxena, Ashish et al. (2011) Inhibition of aldose reductase prevents colon cancer metastasis. Carcinogenesis 32:1259-67

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