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This dissertation, Genetic and Pharmacological Approaches to Study the Role of the Polyol Pathway Enzymes in Diabetic and Ischemic Retinopathy by Kwok-ho, Alvin, Cheung, 張國豪, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled Genetic and pharmacological approaches to study the role of the polyol pathway enzymes in diabetic and ischemic retinopathy Submitted by Cheung Kwok Ho Alvin for the degree of Doctor of Philosophy at The University of Hong Kong in December 2007 Increase in the polyol pathway activity has been shown to play a role in the pathogenesis of diabetic retinopathy, which is thought to be the consequence of ischemia. To overcome the non-specificity and varied bioavailability of inhibitors to the retina, we decided to study effects of aldose reductase (AR) and sorbitol dehydrogenase (SDH), the first and the second enzymes in the polyol pathway, on retinal diabetic and ischemic injury using the previously -/- -/- characterized AR-deficient (AR ) and SDH-deficient (SDH ) mice. To -/- investigate the role of AR in the pathogenesis of diabetic retinopathy, the AR mouse were bred with the diabetic db/db mouse, which is a Type II diabetic mouse model shown to display signs of diabetic retinopathy. Moreover, the -/- -/- AR and SDH mice were also subjected to transient retinal artery occlusion (2 hrs of occlusion and 22 hrs of reperfusion) by intraluminal suture method to illustrate the effects of these enzymes on retina ischemic injury. Treatment of C57BL/6N mice with either AR inhibitor, Fidarestat, or SDH inhibitor, CP-470, 711, was also included to test the efficacy and specificity of the inhibitors on the protection against retinal ischemic injury. To test the possible pathogenic role of AR in the development of diabetic and ischemic retinopathy is mediated via +/+ -/- Muller cell homeostasis, Muller cells isolated from wildtype (AR ) and AR mice or the Muller cell line, rMC-1, treated with Fidarestat was challenged with high concentration of glucose or in vitro ischemia. The retinas of 15 mos. diabetic db/db mice, which showed an over-expression of AR, displayed signs of retinopathy, such as loss of pericytes, blood-retinal barrier breakdown, neuro-retinal apoptosis, glial reactivation, and proliferation of blood vessels, -/- whereas, AR db/db mice did not show such abnormal signs. Also, -/- ischemia-induced neuronal loss and edema were prevented in the retinas of AR -/- mice or C57BL/6N mice treated with Fidarestat. However, SDH mice and C57BL/6N mice treated with SDH inhibitor, CP-470, 711, were not protected against ischemia-induced retinal damage. Inhibition of AR also prevented increased accumulation of myo-inositol and cell death in rMC-1 cells at high level of glucose. In addition, proliferation at high level of glucose and cell +/+ death induced by in vitro ischemia observed in AR Muller cells were reduced -/- in AR Muller cells. These findings indicate that AR is responsible for the early events in the pathogenesis of diabetic retinopathy, leading to a cascade of retinal lesions. Also, AR, but not SDH, in the polyol pathway contributes to the pathogenesis of ischemic retinopathy. Our results also suggest that AR-induced retinal injury under diabetic and ischemic conditions could be mediated via the loss of regulation of Muller cell homeostasis. DOI: 10.5353/th_b3955861 Subjects: PolyolsDiabetic retinopathyEye - Diseases - Genetic aspectsEye - Diseases - PathogenesisMice as laboratory animals

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