March 2012
Volume 53, Issue 14
Free
ARVO Annual Meeting Abstract  |   March 2012
Impairment of the Ubiquitin-Proteasome Pathway in RPE Causes AMD-Related Lesions in Mice
Author Affiliations & Notes
  • Fu Shang
    Human Nutrition Res Ctr on Aging, Tufts University, Boston, Massachusetts
  • Benchun Miao
    Human Nutrition Res Ctr on Aging, Tufts University, Boston, Massachusetts
  • Qingning Bian
    Human Nutrition Res Ctr on Aging, Tufts University, Boston, Massachusetts
  • Allen Taylor
    Human Nutrition Res Ctr on Aging, Tufts University, Boston, Massachusetts
  • Donald E. Smith
    Human Nutrition Res Ctr on Aging, Tufts University, Boston, Massachusetts
  • Janis Lem
    Tufts Medical center, Boston, Massachusetts
  • Paulo Pereira
    Center of Ophthalmology, University of Coimbra, Coimbra, Portugal
  • Footnotes
    Commercial Relationships  Fu Shang, None; Benchun Miao, None; Qingning Bian, None; Allen Taylor, None; Donald E. Smith, None; Janis Lem, None; Paulo Pereira, None
  • Footnotes
    Support  NIH EY 11717 (to FS), EY 13250 (to AT), USDA AFRI Award 2009-35200-05014 (to FS), AHAF grant M2010038 (to FS), grant FCT – PTDC/SAU-OSM/67498/2006 (to PP), and USDA CRIS 1950- 51000-060-02A (to AT)
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 4759. doi:
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    • Get Citation

      Fu Shang, Benchun Miao, Qingning Bian, Allen Taylor, Donald E. Smith, Janis Lem, Paulo Pereira; Impairment of the Ubiquitin-Proteasome Pathway in RPE Causes AMD-Related Lesions in Mice. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4759.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : The ubiquitin-proteasome pathway (UPP) plays important roles in protein quality control and signal transductions. It was reported that activities of the UPP in retina and RPE decrease upon aging and oxidative stress. The objective of this work was to test the hypothesis that impairment of the UPP in RPE contributes to the pathogenesis of AMD-related lesions and to investigate the mechanisms by which impairment of the UPP triggers the development of AMD-related lesions.

Methods: : To impair the function of the UPP in RPE, the RPE-65 promoter was used to drive the expression of K6W-ubiquitin (a dominant negative inhibitor of the UPP) in RPE of transgenic mice. The transgenic mice were crossed back to C57BL/6 background. The retinas of wild type (wt) and transgenic mice were examined by fundus photography at different ages. Retina sections were examined morphologically and immunohistochemically. ARPE-19 cells were used to determine the effects of impairment of the UPP on expression and secretion of pro-angiogenic and pro-inflammatory factors.

Results: : The transgenic mice that express K6W-ubiquitin in RPE developed normally and there were no detectable lesions until 6 months. By 12 months of age, some retina pigment abnormalities were detected by fundus photography. By 18 months of age, ~70% of the transgenic mice showed pigment abnormalities whereas all age-matched wt mice showed normal retinas. Morphological examination of retinal sections showed that there were focal losses of RPE in transgenic mice at 12 months of age. By18 months of age, ~70% of the transgenic mice showed focal choroidal neovascularization. Immunochemical examination of the sections showed that there was enhanced deposition of C3d onto basal side of RPE. In cultured ARPE-19 cells, impairment of the UPP increased the expression and secretion of VEGF and IL-8, but decreased the expression and secretion of complement factor H and MCP-1.

Conclusions: : These data demonstrate that impairment of the UPP in RPE triggers the development of AMD-like lesions in mice, indicating that age-or stress-related decline in UPP function is a contributing factor to AMD pathogenesis. Altered expression and secretion of angiogenic and inflammatory factors by impairment of the UPP appears to be involved in the development of AMD-like lesions.

Keywords: choroid: neovascularization • retinal pigment epithelium • inflammation 
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