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First published online on April 6, 2005
Endocrine Reviews, doi:10.1210/er.2004-0028
A more recent version of this article appeared on May 1, 2005
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Role of aldose reductase and oxidative damage in diabetes and the consequent potential for therapeutic options

Satish K Srivastava*, Kota V Ramana, and Aruni Bhatnagar

Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, TX 77555; Division of Cardiology, Department of Medicine, University of Louisville, Louisville, KY 40202

* To whom correspondence should be addressed. E-mail: ssrivast{at}utmb.edu.

Aldose reductase (AR) is widely expressed aldehyde-metabolizing enzyme. The reduction of glucose by the AR catalyzed polyol pathway has been linked to the development of secondary diabetic complications. Although treatment with AR inhibitors has been shown to prevent tissue injury in animal models of diabetes, the clinical efficacy of these drugs remains to be established. Recent studies suggest that glucose may be an incidental substrate of AR, which appears to be more adept in catalyzing the reduction of a wide range of aldehydes generated from lipid peroxidation. Moreover, inhibition of the enzyme has been shown to increase inflammation-induced vascular oxidative stress and prevent myocardial protection associated with the late phase of ischemic preconditioning. On the basis of these studies several investigators have ascribed an important antioxidant role to the enzyme. Additionally, ongoing work indicates that AR is a critical component of intracellular signaling and inhibition of the enzyme prevents high glucose-, cytokine- or growth factor-induced activation of protein kinase C and NF-{kappa}B. Thus, treatment with AR inhibitors prevents vascular smooth muscle cell growth and endothelial cell apoptosis in culture and inflammation and restenosis in vivo. Additional studies indicate that the antioxidant and signaling roles of AR are interlinked and that AR regulates the PKC-NF-{kappa}B via redox sensitive mechanisms. These data underscore the need for re-evaluating anti-AR interventions for the treatment of diabetic complications. Potentially, the development of newer drugs that selectively inhibit AR-mediated glucose metabolism and signaling, without affecting aldehyde detoxification may be useful in preventing inflammation associated with the development of diabetic complications; particularly micro- and macrovascular diseases.
Key words: Aldose reductase • detoxification • cell signaling • regulation • diabetes




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