Ординатура / Офтальмология / Английские материалы / Retinal and Choroidal Angiogenesis_Penn_2008
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the diabetic animals during the short duration in which they are studied (as compared to the more extensive vaso-obliteration that develops over many years in diabetic patients). In addition, perhaps the diabetes-induced increases in growth factor expression in the animals are not quantitatively great enough to stimulate the neovascular response, or other unknown factors also are required.
6.NONDIABETIC MODELS OF NEOVASCULARIZATION
In the absence of diabetes-induced retinal neovascularization in animal models, investigators have utilized other experimental techniques to study the neovascular response. In support of this experimental approach, there is no evidence at present that diabetes-induced neovascularization of the retina involves signaling pathways distinct from those in the nondiabetic models listed below.
6.1VEGF overexpression
Transgenic mice have been produced that overexpress VEGF in the photoreceptors under control of the rhodopsin promoter. In these animals, neovascularization has been observed to develop. These new vessels originate from the deep capillary bed and extend through the photoreceptor layer to form vascular complexes in the subretinal space (i.e., towards the choroid).121-124 This new vessel growth is in the opposite direction of that seen in diabetic retinopathy (the superficial capillary bed is not affected122). On the other hand, if VEGF is overexpressed in the front of the retina (in lens), abnormal new vessels develop on the surface of the retina.125
Intravitreal injection of VEGF into the eyes of normal cynomolgus monkeys also resulted in diabetic-like lesions, including areas of capillary nonperfusion, vessel dilation and tortuosity, endothelial cell hyperplasia, and preretinal neovascularization.126 The new vessels originated only from superficial veins and venules, and were observed throughout peripheral retina, but not in the posterior pole.
6.2Overexpression of IGF
Normoglycemic/normoinsulinemic transgenic mice overexpressing IGF-1 in the retina developed many alterations characteristic of diabetic retinopathy, including loss of pericytes and thickening of basement membrane of retinal
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capillaries. In mice 6 months and older, venule dilatation, IRMAs, and neovascularization of the retina and vitreous cavity were reported.110
6.3Oxygen-induced retinopathy
Probably the most utilized animal model of preretinal neovascularization is the oxygen-induced retinopathy (OIR) model (see review by Madan and Penn127). In this model, exposure of neonatal animals to elevated concentrations of oxygen impairs development of the normal retinal vasculature, thus resulting in profound retinal ischemia and neovascularization when the animals are removed from the high-oxygen environment. The neovascularization in this model differs from diabetic retinopathy in that the neovascularization in the OIR model occurs acutely in a retina that is not fully differentiated, as compared to the progressive capillary obliteration that develops in the fully differentiated retina in diabetes. Whether or not this difference is important remains to be demonstrated.
6.4Branch vein occlusion
This model differs from OIR in that the retina and the retinal vasculature are fully differentiated when retinal ischemia is induced by occluding some or all branch veins in the retina.128-136 This neovascular response differs from that in diabetes mainly in the acute nature of the ischemia induced by branch vein occlusion.
6.5Koletsky rat
The obese SHR rat (koletsky rat; SHR-k; (f/f)) has a nonsense leptin receptor mutation, and the animals are obese, hyperphagic, hypertensive, hyperlipidemic, insulin-resistant, and infertile.137 These animals exhibit retinal vascular changes that include progressive retinal capillary dropout, increased capillary permeability, and in some animals, preretinal neovascularization.138
7.THERAPIES THAT INHIBIT DIABETIC RETINOPATHY
Capillary occlusion begins early in the course of the retinopathy, and is a major contributor to the progressive retinal ischemia that is believed to drive retinal neovascularization in the proliferative stage. Thus, the increase in
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numbers of acellular and nonperfused capillaries in diabetes likely is causally related to the development of retinal neovascularization in diabetes. Inhibition of the formation of acellular capillaries is expected to inhibit the development of retinal neovascularization and prevent consequent vision loss in diabetes.
A variety of seemingly unrelated therapies have been found to inhibit formation of acellular capillaries and other lesions in diabetic animals (Table 1). The mechanism(s) by which these therapies inhibit retinopathy are not clear at present, due in large part to multiple actions of the various therapies. For example, aminoguanidine originally was viewed solely as an inhibitor of advanced glycation endproduct formation, but now is known also to be a potent inhibitor of iNOS activity. It seems unlikely that there are multiple independent biochemical abnormalities that lead to the development of morphologic lesions characteristic of diabetic retinopathy, so a simpler working hypothesis is that the different therapies are inhibiting a common pathway (albeit at different sites along that pathway) that leads to the lesions. A challenge over the coming years will be to see if this “final common pathway” can be identified.
Table 4-1. Therapies or gene alterations reported to inhibit vascular lesions in diabetic or galactose-fed animals.
|
|
Selected references |
1. |
Insulin |
25, 28, 31 |
2. |
Aminoguanidine |
103-105, 99 |
3. |
Aldose reductase inhibitors |
94, 85, 86, 97, 98, 49 |
4. |
Nerve growth factor |
68, Kern unpublished |
5. |
Antioxidants |
39, 42 |
6. |
Antisense oligos against fibronectin |
102 |
7. |
High-dose aspirin |
105 |
8. |
Pyridoxamine |
43 |
9. |
Benfotiamine |
46 |
10. Deletion of ICAM or CD-18 |
59 |
|
11. PARP inhibitor |
141 |
|
A significant advance was made several years ago by the observation that
retinal capillary cells and neuronal cells were dying by an apoptotic-like process.44,56,69,70,99,139,140 This cell death precedes the appearance of the
classical lesions of diabetic retinopathy, and seems likely to play an important role in the development of the lesions.99 In several therapies studied to date, successful inhibition of capillary cell apoptosis led to inhibition of acellular capillaries and other lesions of the early stages of diabetic retinopathy.99,141 Conversely, failure to inhibit capillary cell apoptosis resulted in no inhibition of the retinopathy.99
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7.1Diabetic retinopathy as a chronic inflammatory disease
Novel insight into the pathogenesis of capillary obliteration and development of diabetic retinopathy recently has come from the recognition that retinas from diabetic animals exhibit biochemical and physiological abnormalities that, in composite, resemble inflammation. These abnormalities include leukostasis, increased expression of adhesion molecules, altered vascular
permeability, and increased production of prostaglandins, nitric oxide, and cytokines.59,105,141-153 Assessing the role of inflammatory-like processes in the
development of retinopathy, and the ability of anti-inflammatory agents to inhibit the retinopathy, is currently an exciting and rapidly moving area of research.
8.FUTURE DIRECTIONS
One of the principal advantages of animal models of retinopathy is that they permit biochemical and physiological studies that are otherwise impractical with human subjects, including, for example, evaluation of potentially hazardous treatments. Upon discovery of each biochemical defect associated with retinopathy, new opportunities arise for screening pharmacological agents for their effects on the retinopathy. For screening, rat and mouse models offer the advantage of low cost and relatively rapid onset of significant anatomic criteria such as capillary cell loss. The mouse model can offer, in addition, unique opportunities for exploring the pathogenesis of retinopathy by genetic manipulation of metabolic pathways and pathophysiological syndromes. At present, these diabetic animal models have not been found to be useful models of preretinal neovascularization, but are excellent models to study the pathogenesis of capillary obliteration and cell death, likely the ultimate causes of the retinal neovascularization in diabetes. Preventing diabetes-induced capillary obliteration from ever occurring in the retina seems likely to be a more beneficial therapeutic goal than merely inhibiting neovascularization in an already damaged and ischemic retina.
ACKNOWLEDGMENTS
This work was funded by PHS grants EY00300 and DK57733, the Medical Research Service of the Department of Veteran Affairs, and the Kristin C. Dietrich Diabetes Research Award.
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REFERENCES
1.R. Klein, B. E. Klein, S. E. Moss, M. D. Davis, and D. D. DeMets, The Wisconsin Epidemiologic Sudy of Diabetic Retinopathy. I. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years, Arch. Ophthalmol. 102, 520-526 (1984).
2.R. Klein, B. E. Klein, S. E. Moss, M. D. Davis, and D. L. DeMets, The Wisconsin Epidemiologic Study of Diabetic Retinopathy. II. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years, Arch. Ophthalmol. 102, 527-532 (1984).
3.M. D. Davis, Diabetic retinopathy. A clinical overview, Diabetes Care 15, 1844-1874 (1992).
4.D. A. Antonetti, E. Lieth, A.J. Barber, and T. W. Gardner, Molecular mechanisms of vascular permeability in diabetic retinopathy, Semin. Ophthalmol. 14, 240-248 (1999).
5.T. A. Ciulla et al., Ocular perfusion abnormalities in diabetes, Acta. Ophthalmol. Scand. 80, 468-477 (2002).
6.G. Bresnick, R. Engerman, M. D. Davis, G. de Venecia, and F. L. Myers, Patterns of ischemia in diabetic retinopathy, Trans. Am. Acad. Ophthalmol. Otolaryngol. 81, 694-709 (1976).
7.M. Yokote, in: Early Diabetes Adv. Metab. Disorders, (Academic Press, 1973) pp. 299-304.
8.M. Kaczurowski, Angiopathy of retinal vessels in diabetic mice, Arch. Ophthal. 84, 316-320 (1970).
9.J. Duhault, F. Lebon, and M. Boulanger, in: 7th Europ. Conf. Microcirculation, (Karger, Aberdeen, 1973) pp. 453-458.
10.A. A. F. Sima, R. Garcia-Salinas, and P. K. Basu, The BB Wistar rat: an experimental model for the study of diabetic retinopathy, Metabolism 32(Suppl. 1), 136-140 (1983).
11.S. Chakrabarti and A. A. F. Sima, Effect of aldose reductase inhibition and insulin treatment on retinal capillary basement membrane thickening in BB rats, Diabetes 38, 1181-1186 (1989).
12.D. Toussaint, Contribution a l’etude anatomique et clinque de la retinopathie diabetique chez l’homme et chez l’animal, Pathologia Europea, 108-148 (1968).
13.H. R. Hausler, T. M. Sibay, and J. Campbell, Retinopathy in a dog following diabetes induced by growth hormone, Diabetes 13, 122-126 (1964).
14.W. Gepts and D. Toussaint, Spontaneous diabetes in dogs and cats, Diabetologia 3, 249-264 (1967).
15.T. M. Sibay and H. R. Hausler, Eye findings in two spontaneously diabetic related dogs,
Am. J. Ophthalmol. 63, 289-294 (1967).
16.N. Laver, W. G. Robison, Jr., and B. C. Hansen, Spontaneously diabetic monkeys as a model for diabetic retinopathy, Invest. Ophthalmol. Vis. Sci. 35(Suppl), 1733 (1994).
17.R. L. Engerman, R. K. Meyer, and J. A. Buesseler, Effects of alloxan diabetes and steroid hypertension on retinal vasculature, Am. J. Ophthalmol. 58, 965-978 (1964).
18.R. L. Engerman et al., Appropriate animal models for research on human diabetes mellitus and its complications. Ocular complications, Diabetes 31(Suppl. 1), 82-88 (1982).
19.R. L. Engerman and T. S. Kern, Retinopathy in animal models of diabetes, Diabetes/ Metabolism Rev. 11, 109-120 (1995).
20.R. L. Engerman and J. M. B. Bloodworth, Jr., Experimental diabetic retinopathy in dogs,
Arch. Ophthalmol. 73, 205-210 (1965).
21.R. L. Engerman, Pathogenesis of diabetic retinopathy, Diabetes 38, 1203-1206 (1989).
22.R. L. Engerman and T. S. Kern, Aldose reductase inhibition fails to prevent retinopathy in diabetic and galactosemic dogs, Diabetes 42, 820-825 (1993).
96 |
T. S. Kern |
23.N. Ashton, Arteriolar involvement in diabetic retinopathy, Brit. J. Ophthal. 37, 282-292 (1953).
24.T. A. Gardiner, A. W. Stitt, H. R. Anderson, and D. B. Archer, Selective loss of vascular smooth muscle cells in the retinal microcirculation of diabetic dogs, Brit. J. Ophthal. 78, 54-60 (1994).
25.R. L. Engerman, J. M. B. Bloodworth, Jr., and S. Nelson, Relationship of microvascular disease in diabetes to metabolic control, Diabetes 26, 760-769 (1977).
26.D. L. Hatchell, R. D. Braun, G. A. Lutty, D. S. McLeod, and C. A. Toth, Progression of diabetic retinopathy in a cat, Invest. Ophthalmol. Vis. Sci. 36, S1067 (1995).
27.R. A. Linsenmeier et al., Retinal hypoxia in long-term diabetic cats, Invest. Ophthalmol. Vis. Sci. 39, 1647-1657 (1998).
28.R. L. Engerman and T. S. Kern, Progression of incipient diabetic retinopathy during good glycemic control, Diabetes 36, 808-812 (1987).
29.Diabetes Control and Complications Trial Research Group, The effect of intensive treatment of diabetes on the development of long-term complications in insulin-dependent diabetes mellitus, N. Engl. J. Med. 329, 977-986 (1993).
30.United Kingdom Prospective Diabetes Study, Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes, Lancet 352, 837-853 (1998).
31.H. P. Hammes et al., Islet transplantation inhibits diabetic retinopathy in the sucrose-fed diabetic Cohen diabetic rat, Invest. Ophthalmol. Vis. Sci. 34, 2092-2096 (1993).
32.T. S. Kern and R. L. Engerman, Comparison of retinal lesions in alloxan-diabetic rats and galactose-fed rats, Curr. Eye Res. 13, 863-867 (1994).
33.H. P. Hammes et al., Aminoguanidine does not inhibit the initial phase of experimental diabetic retinopathy in rats, Diabetologia 38, 269-273 (1995).
34.H. P. Hammes et al., Secondary intervention with aminoguanidine retards the progression of diabetic retinopathy in rat model, Diabetologia 38, 656-660 (1995).
35.T. S. Kern and R. L. Engerman, Galactose-induced retinal microangiopathy in rats,
Invest. Ophthalmol. Vis. Sci. 36, 490-496 (1995).
36.H. P. Hammes et al., Acceleration of experimental diabetic retinopathy in the rat by omega-3 fatty acids, Diabetologia 39, 251-255 (1996).
37.T. S. Kern, R. Kowluru, and R. L. Engerman, in: Lessons from Animal Diabetes, edited by E. Shafrir (Smith-Gordon, London, 1996) pp. 395-408.
38.C. D. Agardh, E. Agardh, H. Zhang, and C. G. Ostenson, Altered endothelial/pericyte ratio in Goto-Kakizaki rat retina, J. Diabetes Complications 11, 158-162 (1997).
39.H. P. Hammes, A. Bartmann, L. Engel, and P. Wulfroth, Antioxidant treatment of experimental diabetic retinopathy in rats with nicanartine, Diabetologia 40, 629-634 (1997).
40.S. H. Kim, Y. K. Chu, O. W. Kwon, S. A. McCune, and F. H. Davidorf, Morphologic studies of the retina in a new diabetic model; SHR/N:Mcc-cp rat, Yonsei Med. J. 39, 453-462 (1998).
41.N. Miyamura, I. A. Bhutto, and T. Amemiya, Retinal capillary changes in Otsuka LongEvans Tokushima fatty rats (spontaneously diabetic strain). Electron-microscopic study, Ophthalmic Res. 31, 358-366 (1999).
42.R. Kowluru, J. Tang, and T. S. Kern, Abnormalities of retinal metabolism in diabetes and galactosemia. VII. Effects of long-term administration of antioxidants on retinal oxidative stress and the development of retinopathy, Diabetes 50, 1938-1942 (2001).
43.A. Stitt et al., The AGE inhibitor pyridoxamine inhibits development of retinopathy in experimental diabetes, Diabetes 51, 2826-2832 (2002).
4. Animal Models of Diabetic Retinopathy |
97 |
44.V. Asnaghi, C. Gerhardinger, T. Hoehn, A. Adeboje, and M. Lorenzi, A role for the polyol pathway in the early neuroretinal apoptosis and glial changes induced by diabetes in the rat, Diabetes 52, 506-511 (2003).
45.T. A. Gardiner, H. R. Anderson, and A. W. Stitt, Inhibition of advanced glycation endproducts protects against retinal capillary basement membrane expansion during longterm diabetes, J. Pathol. 201, 328-333 (2003).
46.H. P. Hammes et al., Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy, Nat. Med. 9, 294-299. (2003).
47.N. Kato, S. Yashima, T. Suzuki, Y. Nakayama, and T. Jomori, Long-term treatment with fidarestat suppresses the development of diabetic retinopathy in STZ-induced diabetic rats, J. Diabetes Complications 17, 374-379 (2003).
48.Z. Y. Lu, I. A. Bhutto, and T. Amemiya, Retinal changes in Otsuka long-evans Tokushima Fatty rats (spontaneously diabetic rat)--possibility of a new experimental model for diabetic retinopathy, Jpn. J. Ophthalmol. 47, 28-35 (2003).
49.Z. Dagher et al., Studies of rat and human retinas predict a role for the polyol pathway in human diabetic retinopathy, Diabetes 53, 2404-2411 (2004).
50.R. A. Kowluru, A. Kowluru, S. Chakrabarti, and Z. Khan, Potential contributory role of H-Ras, a small G-protein, in the development of retinopathy in diabetic rats, Diabetes 53, 775-783 (2004).
51.S. Chakrabarti, A. A. F. Sima, W. J. Tze, and J. Tai, Prevention of diabetic retinal capillary pericyte degeneration and loss by pancreatic islet allograft, Curr. Eye Res. 6, 649-658 (1987).
52.B. I. Gaynes, and J. B. Watkins, III, Comparison of glucose, sorbitol and fructose accumulation in lens and liver of diabetic and insulin-treated rats and mice, Comp. Biochem. Biophys. 92B, 685-690 (1989).
53.F. Morii, M. Hattori, E. Miyasaki, S. Fukuchi, and I. Tsukahara, Histological studies on congenitally diabetic KK mice, J. Ophthalmol. Soc. Japan 25, 372-389 (1974).
54.R. A. Cuthbertson and T. E. Mandel, The effect of murine fetal islet transplants on renal and retinal capillary basement membrane thickness, Transplant Proc. 19, 2919-2921 (1987).
55.A. Agren, G. Rehn, and P. Naeser, Morphology and enzyme activities of the retinal capillaries in streptozotocin-diabetic mice, Acta Ophthalmologica 57, 1065-1069 (1979).
56.S. Mohr, J. Tang, and T. S. Kern, Caspase activation in retinas of diabetic and galactosemic mice and diabetic patients, Diabetes 51, 1172-1179 (2002).
57.R. A. Feit-Leichman et al., The mouse model of diabetic retinopathy: Vascular damage without Müller glial cell activation and neuronal loss, Invest. Ophthalmol. Vis. Sci. 46, 4281-4287 (2004).
58.P. M. Martin, P. Roon, T. K. Van Ells, V. Ganapathy, and S. B. Smith, Death of retinal neurons in streptozotocin-induced diabetic mice, Invest. Ophthalmol. Vis. Sci. 45, 3330-3336 (2004).
59.A. M. Joussen et al., A central role for inflammation in the pathogenesis of diabetic retinopathy, Faseb J. 18, 1450-1452 (2004).
60.H. P. Hammes et al., The relationship of glycaemic level to advanced glycation endproduct (AGE) accumulation and retinal pathology in the spontaneous diabetic hamster, Diabetologia 41, 165-170 (1998).
61.J. M. Bloodworth, Jr. and D. L. Molitor, Ultrastructural aspects of human and canine diabetic retinopathy, Invest. Ophthalmol. 4, 1037-1048 (1965).
62.G. M. Bresnick and M. Palta, Predicting progression of severe proliferative diabetic retinopathy, Arch. Ophthalmol. 105, 810-814 (1987).
98 |
T. S. Kern |
63.G. H. Bresnick and M. Palta, Oscillatory potential amplitudes: Relation to severity of diabetic retinopathy, Arch. Ophthal. 105, 929-933 (1987).
64.G. H. Bresnick, Excitotoxins: A possible new mechanism for the pathogenesis of ischemic retinal damage, Arch. Ophthalmol. 107, 339-341 (1989).
65.G. H. Bresnick, Diabetic retinopathy viewed as a neurosensory disorder, Arch. Ophthalmol. 104, 989-990 (1986).
66.A. A. Sima, W. X. Zhang, P. V. Cherian, and S. Chakrabarti, Impaired visual evoked potential and primary axonopathy of the optic nerve in the diabetic BB/W-rat, Diabetologia 35, 602-607 (1992).
67.M. Kamijo, P. V. Cherian, and A. A. F. Sima, The preventive effect of aldose reductase inhibition on diabetic optic neuropathy in the BB/W rat, Diabetologia 36, 893-898 (1993).
68.H. P. Hammes, H. J. Federoff, and M. Brownlee, Nerve growth factor prevents both neuroretinal programmed cell death and capillary pathology in experimental diabetes, Mol. Medicine 1, 527-534 (1995).
69.A. J. Barber et al., Neural apoptosis in the retina during experimental and human diabetes. Early onset and effect of insulin, J. Clin. Invest. 102, 783-791 (1998).
70.E. Lieth, T. W. Gardner, A. J. Barber, and D. A. Antonetti, Retinal neurodegeneration: early pathology in diabetes, Clin. Experiment Ophthalmol. 28, 3-8 (2000).
71.E. Agardh, A. Bruun, and C. D. Agardh, Retinal glial cell immunoreactivity and neuronal cell changes in rats with STZ-induced diabetes, Curr. Eye Res. 23, 276-284 (2001).
72.Y. Aizu, K. Oyanagi, J. Hu, and H. Nakagawa, Degeneration of retinal neuronal processes and pigment epithelium in the early stage of the streptozotocin-diabetic rats, Neuropathology 22, 161-170 (2002).
73.Y. Aizu et al., Topical instillation of ciliary neurotrophic factor inhibits retinal degeneration in streptozotocin-induced diabetic rats, Neuroreport 14, 2067-2071 (2003).
74.S. H. Park et al., Apoptotic death of photoreceptors in the streptozotocin-induced diabetic rat retina, Diabetologia 46, 1260-1268 (2003).
75.L. L. Kusner, V. P. Sarthy, and S. Mohr, Nuclear translocation of glyceraldehyde-3- phosphate dehydrogenase: a role in high glucose-induced apoptosis in retinal Muller cells,
Invest. Ophthalmol. Vis. Sci. 45, 1553-1561 (2004).
76.E. Lieth et al., Glial reactivity and impaired glutamate metabolism in short-term experimental diabetic retinopathy. The Penn State Retina Research Group, Diabetes 47, 815-820 (1998).
77.M. Mizutani, C. Gerhardinger, and M. Lorenzi, Muller cell changes in human diabetic retinopathy, Diabetes 47, 445-449 (1998).
78.A. J. Barber, D. A. Antonetti, and T. W. Gardner, Altered expression of retinal occludin and glial fibrillary acidic protein in experimental diabetes. The Penn State Retina Research Group, Invest. Ophthalmol. Vis. Sci. 41, 3561-3568 (2000).
79.X. X. Zeng, Y. K. Ng, and E. A. Ling, Neuronal and microglial response in the retina of streptozotocin-induced diabetic rats, Vis. Neurosci. 17, 463-471 (2000).
80.E. Rungger-Brandle, A. A. Dosso, and P. M. Leuenberger, Glial reactivity, an early feature of diabetic retinopathy, Invest. Ophthalmol. Vis. Sci. 41, 1971-1980 (2000).
81.Q. Li, E. Zemel, B. Miller, and I. Perlman, Early retinal damage in experimental diabetes: electroretinographical and morphological observations, Exp. Eye Res. 74, 615-625 (2002).
82.A. J. Barber et al., The Ins2Akita mouse as a model of early retinal complications in diabetes, Invest. Ophthalmol. Vis. Sci. 46, 2210-2218 (2005).
83.R. L. Engerman and T. S. Kern, Experimental galactosemia produces diabetic-like retinopathy, Diabetes 31(Suppl), 26A (1982).
4. Animal Models of Diabetic Retinopathy |
99 |
84.R. L. Engerman and T. S. Kern, Experimental galactosemia produces diabetic-like retinopathy, Diabetes 33, 97-100 (1984).
85.P. F. Kador, Y. Akagi, H. Terubayashi, M. Wyman, and J. H. Kinoshita, Prevention of pericyte ghost formation in retinal capillaries of galactose-fed dogs by aldose reductase inhibitors, Arch. Ophthalmol. 106, 1099-1102 (1988).
86.P. F. Kador et al., Prevention of retinal vessel changes associated with diabetic retinopathy in galactose-fed dogs by aldose reductase inhibitors, Arch. Ophthalmol. 108, 1301-1309 (1990).
87.R. N. Frank, The galactosemic dog. A valid model for both early and late stages of diabetic retinopathy, Arch. Ophthalmol. 113, 275-276 (1995).
88.R. L. Engerman and T. S. Kern, Retinopathy in galactosemic dogs continues to progress after cessation of galactosemia, Arch. Ophthalmol. 113, 355-358 (1995).
89.P. F. Kador, Y. Takahashi, M. Wyman, and F. Ferris, III, Diabeteslike proliferative retinal changes in galactose-fed dogs, Arch. Ophthalmol. 113, 352-354 (1995).
90.T. S. Kern and R. L. Engerman, Vascular lesions in diabetes are distributed nonuniformly within the retina, Exp. Eye Res. 60, 545-549 (1995).
91.H. Neuenschwander, Y. Takahashi, and P. F. Kador, Dose-dependent reduction of retinal vessel changes associated with diabetic retinopathy in galactose-fed dogs by the aldose reductase inhibitor M79175, J. Ocul. Pharmacol. Ther. 13, 517-528 (1997).
92.T. Kobayashi et al., Retinal vessel changes in galactose-fed dogs, Arch. Ophthalmol. 116, 785-789 (1998).
93.P. F. Kador et al., Effect of galactose diet removal on the progression of retinal vessel changes in galactose-fed dogs, Invest. Ophthalmol. Vis. Sci. 43, 1916-1921 (2002).
94.W. G. Robison, Jr., M. Nagata, N. Laver, T. C. Hohman, and J. H. Kinoshita, Diabeticlike retinopathy in rats prevented with an aldose reductase inhibitor, Invest. Ophthalmol. Vis. Sci. 30, 2285-2292 (1989).
95.W. G. Robison, Jr., M. Nagata, T. N. Tillis, N. Laver, and J. H. Kinoshita, Aldose reductase and pericyte-endothelial cell contacts in retina and optic nerve, Invest. Ophthalmol. Vis. Sci. 30, 2293-2299 (1989).
96.W. G. Robison, Jr., Diabetic retinopathy: galactose-fed rat model, Invest. Ophthalmol. Vis. Sci. 36, 4A, 1743-1744 (1995).
97.W. G. Robison, Jr., N. M. Laver, J. L. Jacot, and J. P. Glover, Sorbinil prevention of diabetic-like retinopathy in the galactose-fed rat model, Invest. Ophthalmol. Vis. Sci. 36, 2368-2380 (1995).
98.W. G. Robison, Jr. et al., Diabetic-like retinopathy ameliorated with the aldose reductase inhibitor WAY-121,509, Invest. Ophthalmol. Vis. Sci. 37, 1149-1156 (1996).
99.T. S. Kern et al., Response of capillary cell death to aminoguanidine predicts the development of retinopathy: comparison of diabetes and galactosemia, Invest. Ophthalmol. Vis. Sci. 41, 3972-3978 (2000).
100.R. A. Kowluru, J. Tang, and T. S. Kern, Abnormalities of retinal metabolism in diabetes and experimental galactosemia. VII. Effect of long-term administration of antioxidants on the development of retinopathy, Diabetes 50, 1938-1942 (2001).
101.T. S. Kern and R. L. Engerman, A mouse model of diabetic retinopathy, Arch. Ophthalmol. 114, 986-990 (1996).
102.S. Roy, T. Sato, G. Paryani, and R. Kao, Downregulation of fibronectin overexpression reduces basement membrane thickening and vascular lesions in retinas of galactose-fed rats, Diabetes 52, 1229-1234 (2003).
103.H. P. Hammes, S. Martin, K. Federlin, K. Geisen, and M. Brownlee, Aminoguanidine treatment inhibits the development of experimental diabetic retinopathy, Proc. Natl. Acad. Sci. USA 88, 11555-11558 (1991).
100 |
T. S. Kern |
104.H. P. Hammes et al., Aminoguanidine inhibits the development of accelerated diabetic retinopathy in the spontaneous hypertensive rat, Diabetologia 37, 32-35 (1994).
105.T. S. Kern and R. L. Engerman, Pharmacologic inhibition of diabetic retinopathy: Aminoguanidine and aspirin, Diabetes 50, 1636-1642 (2001).
106.R. N. Frank, R. Amin, A. Kennedy, and T. C. Hohman, An aldose reductase inhibitor and aminoguanidine prevent vascular endothelial growth factor expression in rats with long-term galactosemia, Arch. Ophthalmol. 115, 1036-1047 (1997).
107.L. Yanko, I. C. Michaelson, and A. M. Cohen, The retinopathy of sucrose-fed rats, Israel J. Med. Sci. 8, 1633-1636 (1972).
108.R. Boot-Handford and H. Heath, Identification of fructose as the retinopathic agent associated with the ingestion of sucrose-rich diets in the rat, Metab. 29, 1247-1252 (1980).
109.M. J. Tolentino et al., Intravitreous injections of vascular endothelial growth factor produce retinal ischemia and microangiopathy in an adult primate, Ophthalmology 103, 1820-1828 (1996).
110.J. Ruberte et al., Increased ocular levels of IGF-1 in transgenic mice lead to diabeteslike eye disease, J. Clin. Invest. 113, 1149-1157 (2004).
111.L. A. Wiley, G. R. Rupp, and J. J. Steinle, Sympathetic innervation regulates basement membrane thickening and pericyte number in rat retina, Invest. Ophthalmol. Vis. Sci. 46, 744-748 (2005).
112.I. H. Wallow and R. L. Engerman, Permeability and patency of retinal blood vessels in experimental diabetes, Invest. Ophthalmol. 16, 447-461 (1977).
113.C. J. Moravski et al., The renin-angiotensin system influences ocular endothelial cell proliferation in diabetes: transgenic and interventional studies, Am. J. Pathol. 162, 151-160 (2003).
114.T. Murata et al., The relation between expression of vascular endothelial growth factor and breakdown of the blood-retinal barrier in diabetic rat retinas, Lab. Invest. 74, 819-825 (1996).
115.H. Sone et al., Ocular vascular endothelial growth factor levels in diabetic rats are elevated before observable retinal proliferative changes, Diabetologia 40, 726-730 (1997).
116.H. P. Hammes, J. Lin, R. G. Bretzel, M. Brownlee, and G. Breier, Upregulation of the vascular endothelial growth factor/vascular endothelial growth factor receptor system in experimental background diabetic retinopathy of the rat, Diabetes 47, 401-406 (1998).
117.R. E. Gilbert et al., Vascular endothelial growth factor and its receptors in control and diabetic rat eyes, Lab. Invest. 78, 1017-1027 (1998).
118.Y. Segawa et al., Upregulation of retinal vascular endothelial growth factor mRNAs in spontaneously diabetic rats without ophthalmoscopic retinopathy. A possible participation of advanced glycation end products in the development of the early phase of diabetic retinopathy, Ophthalmic Res. 30, 333-339 (1998).
119.H. Kuang et al., The potential role of IGF-I receptor mRNA in rats with diabetic retinopathy, Chin. Med. J. (Engl) 116, 478-480 (2003).
120.V. Poulaki et al., Insulin-like growth factor-I plays a pathogenetic role in diabetic retinopathy, Am. J. Pathol. 165, 457-469 (2004).
121.N. Okamoto et al., Transgenic mice with increased expression of vascular endothelial growth factor in the retina: a new model of intraretinal and subretinal neovascularization, Am. J. Pathol. 151, 281-291 (1997).
122.S. A. Vinores, N. L. Derevjanik, M. A. Vinores, N. Okamoto, and P. A. Campochiaro, Sensitivity of different vascular beds in the eye to neovascularization and blood-retinal barrier breakdown in VEGF transgenic mice, Adv. Exp. Med. Biol. 476, 129-138 (2000).