In order to understand the possible mechanisms in the glaucoma-related retinopathy, the role of the vasoconstrictor, endothelin-1 (ET-1), receptor for advanced glycation end-products (RAGE) as well as its ligand, Aβ in the degeneration of retinal ganglion cells (RGCs) were studied in experimental models. In addition, the relationship of ET-1, RAGE and Aβ for the RGC protective mechanism of Lycium Barbarum (LB) was also investigated.
In the first part, ET-1 together with its receptors, ETA and ETB, were studied to understand their possible roles in chronic ocular hypertension (COH). The neuronal protective mechanism of LB was also determined by using a well established COH rat model. In normal rats, ET-1 and its receptors, ETA and ETB, were distributed in the retina, vasculature and optic nerve. Interestingly, ET-1 expression was up-regulated after COH. LB could decrease the expression of ET-1 and regulate its receptors (up-regulation of ETB and down-regulation of ETA in vasculature; up-regulation of ETA and down-regulation of ETB in RGCs) under the condition of COH. These data suggested that the RGC protective mechanism of LB might be related to its ability to regulate the biological effects of ET-1.
To investigate the pathogenic effect of ET-1 in glaucoma, in the second part, we used transgenic mice with over-expression of ET-1 on endothelial cells (TET-1 mice). We found that beginning at 10-12 months, TET-1 mice showed a progressive retinal degeneration (loss of RGCs associated with neurons in the inner nuclear layer and outer nuclear layer of the retina) without elevation of the intraocular pressure (IOP). The data demonstrated that TET-1 mice may serve as a potential model to investigate the role of endothelial ET-1 in the pathogenesis of normal tension glaucoma and other degenerative retinopathy.
To investigate whether LB plays a role on neuronal protection other than in COH, in the third part, we used an acute ocular hypertension (AOH)-induced ischemia mouse model. We found that LB could rescue RGCs under AOH insult, associating with blood vessel protection (decreasing the damage of blood-retinal-barriers and rescuing the survival of endothelial cells and pericytes) and inhibiting retinal gliosis. We also found the protective mechanism of LB was closely correlated with down-regulation of the expression of RAGE, ET-1, APP (amyloid precursor protein), AGE (advanced glycation end-product) as well as Aβ; therefore to reduce the damage effects of these RAGE-mediated reactions to the retinal neurons, blood vessels and glial cells involved in the ischemic insult.
Taken together, the present study demonstrated that TET-1 mice may be a potential model for investigating the role of ET-1 in degenerative retinopathies, such as normal tension glaucoma. We also showed the neuronal protective mechanism of LB in vivo was associated with inhibiting the biological effect of ET-1 and down-regulating the damage signaling pathways mediated by the activation of RAGE and its ligands (AGE and Aβ). These results provided further understandings in the mechanism of the glaucoma-related retinopathy. In addition, LB could be a neuroprotective agent to the retina following both chronic and acute injuries. / published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy
| Identifer | oai:union.ndltd.org:HKU/oai:hub.hku.hk:10722/180015 |
| Date | January 2011 |
| Creators | Mi, Xuesong., 米雪松. |
| Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
| Source Sets | Hong Kong University Theses |
| Language | English |
| Detected Language | English |
| Type | PG_Thesis |
| Source | http://hub.hku.hk/bib/B47243922 |
| Rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works., Creative Commons: Attribution 3.0 Hong Kong License |
| Relation | HKU Theses Online (HKUTO) |
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