September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
X-Box Binding Protein 1 (XBP1) is critical for retinal endothelial survival by controlling mitochondrial ROS detoxification in aging and diabetes
Author Affiliations & Notes
  • Sarah Xin Zhang
    Department of Ophthalmology and Ross Eye Institute, The State University of New York at Buffalo, Buffalo, New York, United States
    Department of Biochemistry, The State University of New York at Buffalo, Buffalo, New York, United States
  • Jacey hongjie Ma
    Department of Ophthalmology and Ross Eye Institute, The State University of New York at Buffalo, Buffalo, New York, United States
    Aier School of Ophthalmology, Central South University, Changsha, China
  • Zhanwen He
    Department of Biochemistry, The State University of New York at Buffalo, Buffalo, New York, United States
    Department of Pediatrics , Sun Yat-Sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
  • Maulasri Bhatta
    Department of Ophthalmology and Ross Eye Institute, The State University of New York at Buffalo, Buffalo, New York, United States
    SUNY Eye Institute, The State University of New York, Buffalo, New York, United States
  • Joshua Jianxin Wang
    Department of Ophthalmology and Ross Eye Institute, The State University of New York at Buffalo, Buffalo, New York, United States
    SUNY Eye Institute, The State University of New York, Buffalo, New York, United States
  • Footnotes
    Commercial Relationships   Sarah Zhang, None; Jacey Ma, None; Zhanwen He, None; Maulasri Bhatta, None; Joshua Wang, None
  • Footnotes
    Support  NIH grants EY019949 and EY025061, ADA Research Award 7-11-BS-182, and Unrestricted Grants from Research to Prevent Blindness to the Department of Ophthalmology of University at Buffalo
Investigative Ophthalmology & Visual Science September 2016, Vol.57, No Pagination Specified. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Sarah Xin Zhang, Jacey hongjie Ma, Zhanwen He, Maulasri Bhatta, Joshua Jianxin Wang; X-Box Binding Protein 1 (XBP1) is critical for retinal endothelial survival by controlling mitochondrial ROS detoxification in aging and diabetes. Invest. Ophthalmol. Vis. Sci. 201657(12):.

      Download citation file:


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

      ×
  • Supplements
Abstract

Purpose : Progressive loss of retinal endothelial cells is a central event in the pathogenesis of diabetic retinopathy. Activation of the unfolded protein response (UPR) in response to cell stress has been shown to critically regulate retinal inflammation and vascular leakage at early stages of the disease. In current study, we investigate the role of X-box binding protein 1 (XBP1), a major transcription factor of the UPR, in endothelial cell survival and retinal vascular degeneration in relation to aging and diabetes.

Methods : Primary human retinal endothelial cells (HRECs) and mouse brain endothelial cells (BMECs) isolated from endothelial cell (EC)-specific XBP1 knockout (XBP1EC-/-) mice were used for in vitro study. ER stress, mitochondrial damage, ROS generation, anti-oxidant gene expression, glutathione peroxidase (Gpx) activity, and apoptosis were assessed in cells overexpressing or lacking active XBP1. In vivo, retinal vascular pathologies were evaluated in aged (15 month-old) and streptozotocin-induced diabetic XBP1EC-/- and control mice.

Results : In HRECs blockade of XBP1 activation by pharmacological inhibitor exacerbated ER stress- or high glucose- induced apoptosis. In BMECs conditional deletion of XBP1 gene resulted in impaired cell proliferation and migration, and amplifed apoptosis under high glucose condition. Coincidently, XBP1-negative BMECs manifested reduced mitochondrial membrane potential, increased superoxide generation and lipid peroxidation, decreased Gpx gene expression and activity, and reduced level of glutathione. These changes were significantly reversed by treatment with adenovirus expressing active XBP1. In vivo, aged and diabetic XBP1EC-/- mice showed increased acellular capillary formation, reduced EC number, and less vascular density compared to the corresponding wildtype controls.

Conclusions : These findings suggest an essential role of XBP1 in retinal endothelial cell survival through coordinating the ER and mitochondrial responses to cell stress. Therefore, enhancing the function of XBP1 and its downstream anti-apoptotic pathways may provide novel therapeutic approaches to prevention of vascular damage in diabetic retinopathy and age-related retinal diseases.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×