The polyol pathway enzyme aldose reductase (AR) has been implicated in several pleiotrophic complicationsof 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 current funding period show that AR-catalyzed reduced products of lipid aldehydes-glutathione conjugates (such as GS-DHN, glutathione dihydroxynonane), formed under hyperglycemia-induced oxidative stress, mediate NF-KB and API activation that increases inflammatory markers. We have shown that nitrosation activates and glutathiolation inactivates AR. Our central hypothesis is that by altering the cellular redox state, and inducing post-translational modifications, prolonged diabetes perturbs the redox poise and stress signaling leading to an increase in cytokine production and inflammation which in turn induces or exacerbates secondary diabetic complications. To test this hypothesis, we will extend the studies to understand the mechanistic relationship between hyperglycemia and inflammation and identify the role of AR in cytokine production and inflammation. Specifically our aim is to continue our investigations to further understand the mechanisms by which AR mediates hyperglycemia-induced activation of PKC and TACE that cause TNF-a secretion leading to smooth muscle cell hyperplasia, vascular endothelial cell apoptosis, inflammation, and insulin resistance. Accordingly,the aims are extension of the current grant. Completion of our aims will verify our hypothesis and identify the mechanisms through which AR could mediate hyperglycemia- induced inflammatory signals that cause secondary diabetic complicationsincluding insulin resistance. Also the results of additional structural studies on AR would help us in developing more specific and targeted inhibitor(s) of AR. Thus the aims of the next five years are to: (1) investigate the mechanisms by which reduced lipid aldehydes-glutathione conjugates (such as GS-DHN) in hyperglycemia activate PKC and NF-KB and trigger inflammation;(2) delineate the role of AR in regulating TNF-a production during hyperglycemia;(3) identify protein kinase(s) activated by AR- catalyzed reduced lipid aldehydes-glutathione conjugates (GS-DHN) that phosphorylate PKC;and (4) develop specific and targeted aldose reductase inhibitors. Based on our recent crystal structure of the AR-NADPH-glutathione analogue ternary complex and biochemical analysis of the glutathione binding site of AR, molecular modeling, site-directed mutations will be performed to further probe glutathione binding site and the nature of the interaction between AR and glutathione conjugates. This will help in developing structure-based AR inhibitors which will prevent the binding of GS-HNE without affecting the binding and reduction of toxic lipid aldehydes such as HNE. This approach is potentially important in minimizing the toxicity of AR inhibitors thereby greatly improvingthe therapeutic application of AR inhibitors.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Jones, Teresa L Z
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University of Texas Medical Br Galveston
Schools of Medicine
United States
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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
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
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; 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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