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Diabetes 52:1014-1022, 2003
© 2003 by the American Diabetes Association, Inc.

Diabetes Can Alter the Signal Transduction Pathways in the Lens of Rats

D. Steven Zatechka, Jr1, Peter F. Kador2, Sixto Garcia-Castiñeiras3, and Marjorie F. Lou1

1 Department of Veterinary and Biomedical Sciences and Ophthalmology, University of Nebraska-Lincoln, Lincoln, Nebraska
2 National Eye Institute, Bethesda, Maryland
3 Department of Biochemistry, University of Puerto Rico, San Juan, Puerto Rico

Diabetes is known to affect cataract formation by means of osmotic stress induced by activated aldose reductase in the sorbitol pathway. In addition, alterations in the bioavailability of numerous extralenticular growth factors has been reported and shown to result in various consequences. We have found that the basic fibroblast growth factor (bFGF) accumulates in the vitreous humor of 3- and 8-week diabetic rats. Consequently, the associating signal transduction cascades were severely disrupted, including upregulated phosphorylation of extracellular signal-regulated kinase (ERK) and the common stress-associated mitogen-activated protein kinases p38 and SAPK/JNK. Conversely, under diabetic condition, we observed a dramatic inhibition of phosphatidylinositol-3 kinase activity in lenses obtained from the same animal. Rats treated with the aldose reductase inhibitor AL01576 for the duration of the diabetic condition showed that the diabetes-induced lenticular signaling alterations were normalized, comparable to controls. However, treatment of AL01576 in vitro was ineffective at normalizing the altered constituents in extracted diabetic vitreous after the onset of diabetes. The effect of AL01576 in the high galactose-induced cataract model in vitro was also examined. Administration of AL01576 to lens organ culture normalized the aberrant signaling effects and morphological characteristics associated with in vitro sugar cataract formation. In conclusion, our findings demonstrate diabetes-associated alterations in the lens signal transduction parameters and the effectiveness of AL01576 at normalizing such alterations. The causes for these alterations can be attributed to elevated vitreal bFGF in conjunction with osmotic stress and associated attenuation in redox status of the lens.


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J. Zhou and A. S. Menko
Coordinate Signaling by Src and p38 Kinases in the Induction of Cortical Cataracts
Invest. Ophthalmol. Vis. Sci., July 1, 2004; 45(7): 2314 - 2323.
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Copyright © 2003 by the American Diabetes Association.