The objective of the project is to continue the studies on the biochemical mechanism(s) which leads to the formation of senile and diabetic cataract in human subjects. The studies pertaining to the understanding of the nature and the mechanism of cataractogenesis will include oxidative insult caused by various oxidants such as superoxide and hydroxyl radicals, hydrogen peroxide, and lipid-peroxides, and the role of defense enzymes such as glutathione reductase and peroxidase, superoxide dismutase, catalase and glucose-6-phosphate dehydrogenase in lens under normal conditions as well as during sugar and senile cataractogenesis. Formation of free radicals and their involvement in the sequence of events leading to proteolysis, high molecular weight protein (crystallin) aggregate formation and membrane permeability changes will be studied. The efficacy of various antioxidants such as butylated hydroxy toluene (BHT), allopurinol, oxypurinol and mannitol will be studied in the prevention of sugar and senile cataracts. The studies on aldo-keto reductases will be continued to understand their role in sugar cataractogenesis. Our results indicate that aldose reductase is activated during hyperglycemia and the activated enzyme is glycosylated, leading to an increased reduction of glucose to sorbitol. Further studies will be performed to establish the mechanism and the site of activation of aldose reductase and the physiological significance of glycosylation and activation in the etiology of sugar cataractogenesis. Competition between aldose reductase and glutathione reductase for NADPH in hyperglycemia will also be studied as a possible mechanism of sugar cataractogenesis. All the enzymes of sorbitol-6- phosphate pathway will be purified to homogeneity, their substrate and products identified as well as the properties of these enzymes studied. The amount of glucose metabolized through this pathway and the intermediates as well as the enzymes of the pathway will be quantified in the lens during the development of sugar cataract in experimental animals. The proposed studies will lead to a better understanding of the mechanism of senile and sugar cataractogenesis and the role of sorbitol-6-phosphate pathway in the metabolism of glucose by the lens under normo- and hyperglycemic conditions.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Visual Sciences A Study Section (VISA)
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University of Texas Medical Br Galveston
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Ramana, Kota V; Bhatnagar, Aruni; Srivastava, Sanjay et al. (2006) Mitogenic responses of vascular smooth muscle cells to lipid peroxidation-derived aldehyde 4-hydroxy-trans-2-nonenal (HNE): role of aldose reductase-catalyzed reduction of the HNE-glutathione conjugates in regulating cell growth. J Biol Chem 281:17652-60
Pladzyk, Agnieszka; Ramana, Kota V; Ansari, Naseem H et al. (2006) Aldose reductase prevents aldehyde toxicity in cultured human lens epithelial cells. Exp Eye Res 83:408-16
Pladzyk, Agnieszka; Reddy, Aramati B M; Yadav, Umesh C S et al. (2006) Inhibition of aldose reductase prevents lipopolysaccharide-induced inflammatory response in human lens epithelial cells. Invest Ophthalmol Vis Sci 47:5395-403
Singh, Ranvir; White, Mark A; Ramana, Kota V et al. (2006) Structure of a glutathione conjugate bound to the active site of aldose reductase. Proteins 64:101-10
Ramana, Kota V; Willis, Monte S; White, Michael D et al. (2006) Endotoxin-induced cardiomyopathy and systemic inflammation in mice is prevented by aldose reductase inhibition. Circulation 114:1838-46
Srivastava, Satish K; Ramana, Kota V; Bhatnagar, Aruni (2005) Role of aldose reductase and oxidative damage in diabetes and the consequent potential for therapeutic options. Endocr Rev 26:380-92
Ramana, Kota V; Friedrich, Brian; Tammali, Ravinder et al. (2005) Requirement of aldose reductase for the hyperglycemic activation of protein kinase C and formation of diacylglycerol in vascular smooth muscle cells. Diabetes 54:818-29
Srivastava, Seema; Tammali, Ravinder; Chandra, Deepak et al. (2005) Regulation of lens aldose reductase activity by nitric oxide. Exp Eye Res 81:664-72
Ramana, Kota V; Bhatnagar, Aruni; Srivastava, Satish K (2004) Aldose reductase regulates TNF-alpha-induced cell signaling and apoptosis in vascular endothelial cells. FEBS Lett 570:189-94
Ramana, Kota V; Bhatnagar, Aruni; Srivastava, Satish K (2004) Inhibition of aldose reductase attenuates TNF-alpha-induced expression of adhesion molecules in endothelial cells. FASEB J 18:1209-18

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