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Table 2. Genetic modifications found to inhibit diabetes-induced capillary degeneration in animals
Gene modification |
Target |
Presumed action |
References |
Cu/Zn superoxide |
Superoxide dismutase |
Oxidative stress |
[117] |
dismutase−/− |
|
|
|
Mn superoxide |
Superoxide dismutase |
Oxidative stress |
[118] |
dismutase−/− |
|
|
|
CD-18−/− |
Leukocyte adherence |
Inflammation |
[33] |
ICAM-1−/− |
Leukocyte adherence |
Inflammation |
[33] |
IL-1b receptor−/− |
IL-1b signaling |
Inflammation |
[94] |
iNOS−/− |
Nitric oxide production |
Inflammation |
[44] |
5-Lipoxygenase−/− |
Eicosenoid production |
Inflammation |
[45] |
retinas have at least some degenerate, nonperfused remnants of vessels, and occasional vessels likely become occluded or nonfunctional also throughout life. Diabetes greatly accelerates this process, but prolonged exposure to the abnormal milieu of diabetes (approximately 6 months in rodents, 3 or more years in dogs and other larger mammals, and many years in patients) still is required before the diabetes-induced vasoobliteration becomes clearly greater than normal. Why this prolonged interval is required before the degenerative process become apparent remains a mystery, but understanding it likely will provide valuable information into understanding the pathogenesis of the retinopathy.
Metabolic memory. Capillary degeneration has been observed to continue on for at least some interval after restoration of euglycemia in diabetic dogs [65] and rats [80]. Although not specifically focusing on capillary degeneration, retinopathy likewise was found to progress for about a year in diabetic patients after reinstitution of glycemic control [59]. Various molecular changes also have been found to show this “memory” after prior exposure to elevated glucose concentration [81–84], but their relevance to the vascular degeneration of diabetic retinopathy has not been clearly established.
WHAT IS THE RELATION BETWEEN THE RETINAL VASCULATURE AND NEURONAL RETINA STRUCTURE AND FUNCTION IN DIABETES?
Like other neural tissues, metabolic demand by the neural retina influences the retinal vasculature to regulate blood flow to that tissue [85–87]. Conversely, delivery of oxygen and nutrients and removal of waste by the vasculature influence function of the neural retina. Thus, there is neurovascular coupling which can become altered in diabetes [88]. In a very interesting study, the disruption of that coupling led to protection of the retinal vasculature in diabetes. As expected, the density of the retinal vasculature in wild-type control animals diabetic for many months became subnormal, but this capillary degeneration did not develop in diabetic mice having photoreceptor degeneration (rhodopsin knockout mice) [89]. Thus, the outer retina seemed to somehow influence the retinal
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149 |
vasculature (possibly via effects on metabolism by the inner retina), and loss of the outer retina protected the vasculature despite continued exposure to hyperglycemia. In contrast to this report, however, degeneration of retinal neurons in a different model of retinal degeneration (transgenic rat overexpressing a mutant cilia gene polycystin-2) resulted in increased degeneration of retinal capillaries [90]. The neuronal and vascular components of the retina clearly are interactive, but the extent of that interaction under pathologic circumstances requires additional investigation.
Although diabetes-induced defects in metabolism of retinal neurons might impair vision in diabetes independent of vascular disease, occlusion of retinal vessels is closely associated with detrimental effects of diabetes on visual function. The extent of retinal capillary nonperfusion detected by fluorescein angiography has been associated with a reduction in retinal sensitivity as assessed by microperimetry [91]. In addition, diabetic patients with extensive retinal arteriolar and capillary obstruction developed an ischemic maculopathy that resulted in severe loss of visual acuity in some eyes [92]. Whether this is due solely to the vascular nonperfusion or associated neuronal dysfunction is not clear.
CONCLUSION
Vascular abnormalities are major contributors to the morbidity resulting from longstanding diabetes in patients, and capillary nonperfusion and degeneration are especially important in the progression the advanced, proliferative stages of the retinopathy. Clinical attention has focused especially on inhibiting the abnormalities (such as neovascularization and retinal edema) that can have immediate effects on visual impairment, but appreciable retinal vascular damage already will have occurred by focusing on these late stages of the disease. Success is now being made also in the earlier stages of the retinopathy to inhibit capillary degeneration, with hopes that inhibiting the early damage will inhibit development of the more advanced stages of the retinopathy.
ACKNOWLEDGMENT
This work was funded by PHS grant EY00300 and a grant from the Medical Research Service of the Department of Veteran Affairs.
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