. Prolonged diabetes causes major complications in tissues which do not require insulin for transport of glucose, including hyperglycemia-induced neuropathy, retinopathy, nephropathy, epitheliopathy, and cataractogenesis. However, the mechanisms of hyperglycemia-induced cell injury are poorly understood. The first enzyme of the polyol pathway, aldose reductase (AR), has been implicated in diabetic complications because use of aldose reductase inhibitors (ARIs) prevents, reduces, or, to some extent, reverses hyperglycemia-induced cataractogenesis, neuropathy, and retinopathy. Increased AR activity in hyperglycemia has been attributed to activation and/or induction of the enzyme. However, neither the mechanisms of induction nor of activation are well understood. In addition, all the ARIs presently known inhibit both AR and aldehyde reductase, and both enzymes have overlapping substrate specificities. Aldehyde reductase may be important for reducing biogenic amines and a number of dicarbonyl compounds. Therefore, for understanding and managing diabetic complications, it is necessary to elucidate the physicochemical properties of AR and its regulation and physiological roles, along with the properties of aldehyde reductase. We propose to continue our studies on the structural and kinetic properties of AR and aldehyde reductase, and on the regulation of AR under normo-glycemic and hyperglycemic conditions. We will determine the chemical catalytic mechanisms of aldehyde reduction by these enzymes, their mechanisms of inhibitor and substrate interactions, and the sequences of their substrate binding sites. The residues involved in substrate and inhibitor binding, inactivation of aldose reductase and in the chemical reactions will be studied by using site directed mutagenesis. The AR activity increases in hyperglycemia, and the reaction kinetics and inhibitor sensitivity also change. The roles of oxidation, glycation and induction will be examined to understand the mechanism(s) of activation, deactivation and increased transcription of AR during hyperglycemia. We will use a hyperglycemic animal model and cultured neuroblastoma cells to assess the contributions of oxidative stress to tissue injury, perhaps caused by increased free radicals and/or decreased defense capacity against oxidants and polyols. Our studies will help in understanding the role of AR in the etiology of diabetic complications, and will provide a logical approach to treating or preventing the development of such complications.
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| 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 |
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| 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 |
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| 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 |
| Yadav, Umesh C S; Ramana, Kota V; Srivastava, Satish K (2011) Aldose reductase inhibition suppresses airway inflammation. Chem Biol Interact 191:339-45 |
| Yadav, Umesh C S; Shoeb, Mohammad; Srivastava, Satish K et al. (2011) Amelioration of experimental autoimmune uveoretinitis by aldose reductase inhibition in Lewis rats. Invest Ophthalmol Vis Sci 52:8033-41 |
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