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An Aldose Reductase Inhibitor and Aminoguanidine Prevent Vascular Endothelial Growth Factor Expression in Rats With Long-term Galactosemia

An Aldose Reductase Inhibitor and Aminoguanidine Prevent Vascular Endothelial Growth Factor... Abstract Objective: To study the effects of an aldose reductase inhibitor (ARI-509, Wyeth-Ayerst, Princeton, NJ) and aminoguanidine (AMG), agents that have been reported to prevent or delay diabetic retinopathy, on retinal vascular abnormalities and the immunocytochemical expression in the retina of vascular endothelial growth factor (VEGF) in rats maintained for up to 2 years on a 50% galactose diet. Methods: Albino rats were placed on a control diet, a diet containing 50% galactose, or the 50% galactose diet containing either ARI-509 or AMG. Treatment with ARI-509 or AMG was initiated at the beginning of the experiment or after 12 months of galactose feeding. After 22 to 24 months, the rats were killed and the retinal vasculature from half of one eye was isolated by trypsinelastase digestion for semiquantitative evaluation of retinal vascular lesions. The other half of the retina was prepared for immunocytochemistry and stained for the presence of VEGF, factor VIII, vimentin, and glial fibrillary acidic protein. Red blood cells, sciatic nerves, and a portion of the retina from the second eye were assayed for glucose, galactose, fructose, sorbitol, galactitol, and myo-inositol. Red blood cells were also assayed for galactosylated hemoglobin. Results: Galactose-fed animals developed a vascular retinopathy characterized by severe cellular loss in the retinal capillaries and intensification of periodic acid-Schiff staining of the vascular basement membranes. Some animals also displayed dilation and hypercellularity of vessels in the posterior retina. These changes were substantially reduced in animals receiving ARI-509 from the beginning of the galactose diet, but were unaffected in all of the other treatment groups. None of the rats receiving ARI-509 or AMG treatment, whether initiated from the onset or after 12 months of galactosemia, demonstrated VEGF immunoreactivity. With the exception of the animals receiving ARI-509 from the beginning of the experiment, all of the galactose-fed animals developed dense cataracts within 6 weeks of the beginning of the galactose diet. Galactitol levels in animals receiving ARI-509 were 86% to 93% lower in red blood cells, retina, and sciatic nerve than those in the other galactosefed groups. Conclusions: Although ARI-509 and AMG have different abilities to delay or prevent the diabetic-like retinopathy in galactosemic rats, even when substantial retinal microvascular acellularity occurs, both drugs prevent the immunocytochemical expression of VEGF. These results suggest that factors other than hypoxia may be responsible for VEGF expression in the retina, and that aldose reductase inhibitors and AMG have potential roles in preventing such expression and, thus, perhaps preventing retinal neovascularization. References 1. Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders . N Engl J Med . 1994;331:1480-1487.Crossref 2. Adamis AP, Miller JW, Bernal M-T, et al. Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy . Am J Ophthalmol . 1994;118:445-450. 3. Pe'er J, Shweiki D, Itin A, Hemo I, Gnessin H, Keshet E. Hypoxia-induced expression of vascular endothelial growth factorlike activity in proliferative diabetic retinopathy . Arch Ophthalmol . 1994;112:1476-1482.Crossref 4. Malecaze F, Clamens S, Simorre-Pinatel V, et al. Detection of vascular endothelial growth factor messenger RNA and vascular endothelial growth factor-like activity in proliferative diabetic retinopathy . Arch Ophthalmol . 1994;112:1476-1482.Crossref 5. Miller JW, Adamis AP, Shima DT, et al. Vascular endothelial growth factor/vascular permeability factor is temporally and spatially correlated with ocular angiogenesis in a primate model . Am J Pathol . 1994;145:574-584. 6. Pierce EA, Avery RL, Foley ED, Aiello LP, Smith LE. Vascular endothelial growth factor/vascular permeability factor expression in a mouse model of retinal neovascularization . Proc Natl Acad Sci U S A . 1995;92:905-909.Crossref 7. Aiello LP, Pierce EA, Foley ED, et al. Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins . Proc Natl Acad Sci U S A . 1995;92:10457-10461.Crossref 8. Adamis AP, Shima DT, Tolentino MJ, et al. Inhibition of vascular endothelial growth factor prevents retinal ischemia-associated iris neovascularization in a nonhuman primate . Arch Ophthalmol . 1996;114:66-71.Crossref 9. Robinson GS, Pierce EA, Rook SL, Foley E, Webb R, Smith LE. Oligodeoxynucleotides inhibit retinal neovascularization in a murine model of proliferative retinopathy . Proc Natl Acad Sci U S A . 1996;93:4851-4856.Crossref 10. Shweiki D, Itin A, Softer D, Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis . Nature . 1992;359:843-845.Crossref 11. Henkind P. Ocular neovascularization . Am J Ophthalmol . 1978;85:287-301. 12. Patz A. Studies on retinal neovascularization . Invest Ophthalmol Vis Sci . 1980;19:1133-1138. 13. Robison WG Jr, Nagata M, Laver N, Hohman TC, Kinoshita JH. Diabeticlike retinopathy in rats prevented with an aldose reductase inhibitor . Invest Ophthalmol Vis Sci . 1989;30:2285-2292. 14. Kern TS, Engerman RL. Galactose-induced retinal microangiopathy in rats . Invest Ophthalmol Vis Sci . 1995;36:490-496. 15. Kohner EM, Henkind P. Correlation of fluorescein angiogram and retinal digest in diabetic retinopathy . Am J Ophthalmol . 1970;69:403-414. 16. Hammes H-P, Martin S, Federlin K, Geisen K, Brownlee M. Aminoguanidine treatment inhibits the development of experimental diabetic retinopathy . Proc Natl Acad Sci U S A . 1991;88:11555-11558.Crossref 17. Kuwabara T, Cogan DG. Studies of retinal vascular patterns, part I: normal architecture . Arch Ophthalmol . 1960;64:904-911.Crossref 18. Laver NM, Robison WG Jr, Pfeffer BA. Novel procedures for isolating intact retinal vascular beds from diabetic humans and animal models . Invest Ophthalmol Vis Sci . 1993;34:2097-2104. 19. Robison WG Jr, Laver NM, Jacot JL, et al. Diabeticlike retinopathy ameliorated with the aldose reductase inhibitor WAY-121,509 . Invest Ophthalmol Vis Sci . 1996;37:1149-1156. 20. Guerrant GO, Moss CW. Determination of monosaccharides as aldonitrile Omethyloxime, alditol and cyclitol acetate derivatives by gas chromatography . Anal Chem . 1984;56:633-638.Crossref 21. Van Kampel EJ, Zijlstra WG. Standardization of hemoglobinometry, II: the hemoglobin cyanide method . Clin Chem Acta . 1961;6:538-544.Crossref 22. Cogan DG, Toussaint D, Kuwabara T. Studies of retinal vascular patterns, IV: diabetic retinopathy . Arch Ophthalmol . 1961;66:366-378.Crossref 23. Bignami A, Dahl D. The radial glia of Müller in the rat retina and their response to injury: an immunofluorescence study with antibodies to the glial fibrillary acidic (GFA) protein . Exp Eye Res . 1979;28:63-69.Crossref 24. Lewis GP, Matsumoto B, Fisher SK. Changes in the organization and expression of cytoskeletal proteins during retinal degeneration induced by retinal detachment . Invest Ophthalmol Vis Sci . 1995;36:2404-2416. 25. Engerman RL, Kern TS. Progression of incipient diabetic retinopathy during good glycemic control . Diabetes . 1987;36:808-812.Crossref 26. Engerman RL, Kern TS. Retinopathy in galactosemic dogs continues to progress after cessation of galactosemia . Arch Ophthalmol . 1994;113:355-358.Crossref 27. Lerman S. Carbohydrate metabolism in the rat lens as related to the age of the animal . Arch Ophthalmol . 1961;65:181-183.Crossref 28. Kim I, Tolentino MJ, Miller JW, Adamis AP. Constitutive VEGF mRNA expression in the tissues of normal adult eyes . Invest Ophthalmol Vis Sci . 1996;37:S792. ARVO Abstract. 29. Stone J, Itin A, Alon T, et al. Development of retinal vasculature is mediated by hypoxia-induced vascular endothelial growth factor (VEGF) expression by neuroglia . J Neurosci . 1995;15:4738-4747. 30. Amin RH, Frank RN, Kennedy A, Eliott E, Puklin JE, Abrams GW. Vascular endothelial growth factor is present in glial cells of the retina and optic nerve of human subjects with nonproliferative diabetic retinopathy . Invest Ophthalmol Vis Sci . 1997;38:36-47. 31. Lutty GA, McLeod DS, Merges C, Diggs A, Plouét J. Localization of vascular endothelial growth factor in human retina and choroid . Arch Ophthalmol . 1996;114:971-977.Crossref 32. Frank RN, Keirn RJ, Kennedy A, Frank KW. Galactose-induced retinal capillary basement membrane thickening: prevention by sorbinil . Invest Ophthalmol Vis Sci . 1983;24:1519-1524. 33. Robison WG Jr, Kador PF, Kinoshita JH. Retinal capillaries: basement membrane thickening by galactosemia prevented with aldose reductase inhibitor . Science . 1983;221:1177-1179.Crossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Ophthalmology American Medical Association

An Aldose Reductase Inhibitor and Aminoguanidine Prevent Vascular Endothelial Growth Factor Expression in Rats With Long-term Galactosemia

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Publisher
American Medical Association
Copyright
Copyright © 1997 American Medical Association. All Rights Reserved.
ISSN
0003-9950
eISSN
1538-3687
DOI
10.1001/archopht.1997.01100160206011
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Abstract

Abstract Objective: To study the effects of an aldose reductase inhibitor (ARI-509, Wyeth-Ayerst, Princeton, NJ) and aminoguanidine (AMG), agents that have been reported to prevent or delay diabetic retinopathy, on retinal vascular abnormalities and the immunocytochemical expression in the retina of vascular endothelial growth factor (VEGF) in rats maintained for up to 2 years on a 50% galactose diet. Methods: Albino rats were placed on a control diet, a diet containing 50% galactose, or the 50% galactose diet containing either ARI-509 or AMG. Treatment with ARI-509 or AMG was initiated at the beginning of the experiment or after 12 months of galactose feeding. After 22 to 24 months, the rats were killed and the retinal vasculature from half of one eye was isolated by trypsinelastase digestion for semiquantitative evaluation of retinal vascular lesions. The other half of the retina was prepared for immunocytochemistry and stained for the presence of VEGF, factor VIII, vimentin, and glial fibrillary acidic protein. Red blood cells, sciatic nerves, and a portion of the retina from the second eye were assayed for glucose, galactose, fructose, sorbitol, galactitol, and myo-inositol. Red blood cells were also assayed for galactosylated hemoglobin. Results: Galactose-fed animals developed a vascular retinopathy characterized by severe cellular loss in the retinal capillaries and intensification of periodic acid-Schiff staining of the vascular basement membranes. Some animals also displayed dilation and hypercellularity of vessels in the posterior retina. These changes were substantially reduced in animals receiving ARI-509 from the beginning of the galactose diet, but were unaffected in all of the other treatment groups. None of the rats receiving ARI-509 or AMG treatment, whether initiated from the onset or after 12 months of galactosemia, demonstrated VEGF immunoreactivity. With the exception of the animals receiving ARI-509 from the beginning of the experiment, all of the galactose-fed animals developed dense cataracts within 6 weeks of the beginning of the galactose diet. Galactitol levels in animals receiving ARI-509 were 86% to 93% lower in red blood cells, retina, and sciatic nerve than those in the other galactosefed groups. Conclusions: Although ARI-509 and AMG have different abilities to delay or prevent the diabetic-like retinopathy in galactosemic rats, even when substantial retinal microvascular acellularity occurs, both drugs prevent the immunocytochemical expression of VEGF. These results suggest that factors other than hypoxia may be responsible for VEGF expression in the retina, and that aldose reductase inhibitors and AMG have potential roles in preventing such expression and, thus, perhaps preventing retinal neovascularization. References 1. Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders . N Engl J Med . 1994;331:1480-1487.Crossref 2. Adamis AP, Miller JW, Bernal M-T, et al. Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy . Am J Ophthalmol . 1994;118:445-450. 3. Pe'er J, Shweiki D, Itin A, Hemo I, Gnessin H, Keshet E. Hypoxia-induced expression of vascular endothelial growth factorlike activity in proliferative diabetic retinopathy . Arch Ophthalmol . 1994;112:1476-1482.Crossref 4. Malecaze F, Clamens S, Simorre-Pinatel V, et al. Detection of vascular endothelial growth factor messenger RNA and vascular endothelial growth factor-like activity in proliferative diabetic retinopathy . Arch Ophthalmol . 1994;112:1476-1482.Crossref 5. Miller JW, Adamis AP, Shima DT, et al. Vascular endothelial growth factor/vascular permeability factor is temporally and spatially correlated with ocular angiogenesis in a primate model . Am J Pathol . 1994;145:574-584. 6. Pierce EA, Avery RL, Foley ED, Aiello LP, Smith LE. Vascular endothelial growth factor/vascular permeability factor expression in a mouse model of retinal neovascularization . Proc Natl Acad Sci U S A . 1995;92:905-909.Crossref 7. Aiello LP, Pierce EA, Foley ED, et al. Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins . Proc Natl Acad Sci U S A . 1995;92:10457-10461.Crossref 8. Adamis AP, Shima DT, Tolentino MJ, et al. Inhibition of vascular endothelial growth factor prevents retinal ischemia-associated iris neovascularization in a nonhuman primate . Arch Ophthalmol . 1996;114:66-71.Crossref 9. Robinson GS, Pierce EA, Rook SL, Foley E, Webb R, Smith LE. Oligodeoxynucleotides inhibit retinal neovascularization in a murine model of proliferative retinopathy . Proc Natl Acad Sci U S A . 1996;93:4851-4856.Crossref 10. Shweiki D, Itin A, Softer D, Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis . Nature . 1992;359:843-845.Crossref 11. Henkind P. Ocular neovascularization . Am J Ophthalmol . 1978;85:287-301. 12. Patz A. Studies on retinal neovascularization . Invest Ophthalmol Vis Sci . 1980;19:1133-1138. 13. Robison WG Jr, Nagata M, Laver N, Hohman TC, Kinoshita JH. Diabeticlike retinopathy in rats prevented with an aldose reductase inhibitor . Invest Ophthalmol Vis Sci . 1989;30:2285-2292. 14. Kern TS, Engerman RL. Galactose-induced retinal microangiopathy in rats . Invest Ophthalmol Vis Sci . 1995;36:490-496. 15. Kohner EM, Henkind P. Correlation of fluorescein angiogram and retinal digest in diabetic retinopathy . Am J Ophthalmol . 1970;69:403-414. 16. Hammes H-P, Martin S, Federlin K, Geisen K, Brownlee M. Aminoguanidine treatment inhibits the development of experimental diabetic retinopathy . Proc Natl Acad Sci U S A . 1991;88:11555-11558.Crossref 17. Kuwabara T, Cogan DG. Studies of retinal vascular patterns, part I: normal architecture . Arch Ophthalmol . 1960;64:904-911.Crossref 18. Laver NM, Robison WG Jr, Pfeffer BA. Novel procedures for isolating intact retinal vascular beds from diabetic humans and animal models . Invest Ophthalmol Vis Sci . 1993;34:2097-2104. 19. Robison WG Jr, Laver NM, Jacot JL, et al. Diabeticlike retinopathy ameliorated with the aldose reductase inhibitor WAY-121,509 . Invest Ophthalmol Vis Sci . 1996;37:1149-1156. 20. Guerrant GO, Moss CW. Determination of monosaccharides as aldonitrile Omethyloxime, alditol and cyclitol acetate derivatives by gas chromatography . Anal Chem . 1984;56:633-638.Crossref 21. Van Kampel EJ, Zijlstra WG. Standardization of hemoglobinometry, II: the hemoglobin cyanide method . Clin Chem Acta . 1961;6:538-544.Crossref 22. Cogan DG, Toussaint D, Kuwabara T. Studies of retinal vascular patterns, IV: diabetic retinopathy . Arch Ophthalmol . 1961;66:366-378.Crossref 23. Bignami A, Dahl D. The radial glia of Müller in the rat retina and their response to injury: an immunofluorescence study with antibodies to the glial fibrillary acidic (GFA) protein . Exp Eye Res . 1979;28:63-69.Crossref 24. Lewis GP, Matsumoto B, Fisher SK. Changes in the organization and expression of cytoskeletal proteins during retinal degeneration induced by retinal detachment . Invest Ophthalmol Vis Sci . 1995;36:2404-2416. 25. Engerman RL, Kern TS. Progression of incipient diabetic retinopathy during good glycemic control . Diabetes . 1987;36:808-812.Crossref 26. Engerman RL, Kern TS. Retinopathy in galactosemic dogs continues to progress after cessation of galactosemia . Arch Ophthalmol . 1994;113:355-358.Crossref 27. Lerman S. Carbohydrate metabolism in the rat lens as related to the age of the animal . Arch Ophthalmol . 1961;65:181-183.Crossref 28. Kim I, Tolentino MJ, Miller JW, Adamis AP. Constitutive VEGF mRNA expression in the tissues of normal adult eyes . Invest Ophthalmol Vis Sci . 1996;37:S792. ARVO Abstract. 29. Stone J, Itin A, Alon T, et al. Development of retinal vasculature is mediated by hypoxia-induced vascular endothelial growth factor (VEGF) expression by neuroglia . J Neurosci . 1995;15:4738-4747. 30. Amin RH, Frank RN, Kennedy A, Eliott E, Puklin JE, Abrams GW. Vascular endothelial growth factor is present in glial cells of the retina and optic nerve of human subjects with nonproliferative diabetic retinopathy . Invest Ophthalmol Vis Sci . 1997;38:36-47. 31. Lutty GA, McLeod DS, Merges C, Diggs A, Plouét J. Localization of vascular endothelial growth factor in human retina and choroid . Arch Ophthalmol . 1996;114:971-977.Crossref 32. Frank RN, Keirn RJ, Kennedy A, Frank KW. Galactose-induced retinal capillary basement membrane thickening: prevention by sorbinil . Invest Ophthalmol Vis Sci . 1983;24:1519-1524. 33. Robison WG Jr, Kador PF, Kinoshita JH. Retinal capillaries: basement membrane thickening by galactosemia prevented with aldose reductase inhibitor . Science . 1983;221:1177-1179.Crossref

Journal

Archives of OphthalmologyAmerican Medical Association

Published: Aug 1, 1997

References