July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
Loss of Xbp1 leads to early-onset retinal neurodegeneration in a mouse model of type I diabetes
Author Affiliations & Notes
  • Todd McLaughlin
    Department of Ophthalmology, University at Buffalo, State University of New York, Buffalo, New York, United States
    Ross Eye Institute, Buffalo, New York, United States
  • Don Seyfried
    Department of Ophthalmology, University at Buffalo, State University of New York, Buffalo, New York, United States
  • Manhal Siddiqi
    Department of Ophthalmology, University at Buffalo, State University of New York, Buffalo, New York, United States
  • Joshua Jianxin Wang
    Department of Ophthalmology, University at Buffalo, State University of New York, Buffalo, New York, United States
    Ross Eye Institute, Buffalo, New York, United States
  • Sarah Xin Zhang
    Department of Ophthalmology, University at Buffalo, State University of New York, Buffalo, New York, United States
    Ross Eye Institute, Buffalo, New York, United States
  • Footnotes
    Commercial Relationships   Todd McLaughlin, None; Don Seyfried, None; Manhal Siddiqi, None; Joshua Wang, None; Sarah Zhang, None
  • Footnotes
    Support  NIH/NEI grants EY019949 and EY025061, and an Unrestricted Grant to the Department of Ophthalmology, SUNY-Buffalo, from Research to Prevent Blindness.
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 6424. doi:https://doi.org/
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      Todd McLaughlin, Don Seyfried, Manhal Siddiqi, Joshua Jianxin Wang, Sarah Xin Zhang; Loss of Xbp1 leads to early-onset retinal neurodegeneration in a mouse model of type I diabetes. Invest. Ophthalmol. Vis. Sci. 2019;60(9):6424. doi: https://doi.org/.

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

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Abstract

Purpose : X-box binding protein 1 (Xbp1) is a major transcription factor responsible for the adaptive unfolded protein response (UPR) to maintain protein homeostasis in cells undergoing endoplasmic reticulum (ER) stress. The purpose of this study is to determine the role of Xbp1-mediated UPR in retinal neuronal survival and function in a mouse model of type 1 diabetes.

Methods : Conditional knockout (cKO) of Xbp1 in retinal neurons was achieved by crossing XBP1 floxed mice with a retina-specific Cre-recombinase line (Chx10-Cre). Diabetes was induced with streptozotocin (STZ) in 8 week-old wild type (WT) and cKO mice. Thicknesses of retinal layers, numbers of retinal ganglion cells (RGCs), and ribbon synapses were assessed by immunohistochemistry with various markers in retinal sections. Retinal function was assessed by electroretinogram (ERG) prior to, 1 week after, and 20 weeks after the onset of diabetes.

Results : There was no significant difference in blood glucose and body weight in diabetic cKO and WT mice. Retinal function and morphology, across all parameters examined, were indistinguishable in non-diabetic Xbp1 cKO and WT mice. After 20 weeks of hyperglycemia, diabetic cKO mice demonstrated a significantly diminished b-wave in both photopic and scotopic ERGs, compared to diabetic WT mice and to age-matched non-diabetic cKO and WT mice. There was no difference in a-waves or implicit times between groups. Morphologically, the retinas of diabetic mice were thinner than the non-diabetics. Compared to diabetic WT mice, diabetic cKO mice exhibited significantly greater reduction in retinal thickness and ONL thickness and decrease in photoreceptor nuclei. Furthermore, diabetic cKO mice had fewer ribbon synapses in OPL and reduced number of RGCs compared to diabetic WT mice and to non-diabetic mice. Additionally, there was a significant upregulation of glial fibrillary acidic protein (GFAP) expression in Müller cell processes in diabetic cKO retinas compared to diabetic WT retinas and non-diabetic retinas.

Conclusions : Loss of Xbp1 in retinal neurons leads to accelerated retinal deterioration and functional deficits in diabetic retinopathy. These findings suggest that Xbp1-mediated UPR is crucial to maintaining retinal integrity and function under disease conditions such as diabetes.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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