July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Inner retinal injury induced by acute elevation of IOP is mediated independently of Shp2 silencing effects
Author Affiliations & Notes
  • mojdeh abbasi
    Clinical Medicine, Macquarie University, Sydney, New South Wales, Australia
  • Vivek Kumar Gupta
    Clinical Medicine, Macquarie University, Sydney, New South Wales, Australia
  • Nitin Chitranshi
    Clinical Medicine, Macquarie University, Sydney, New South Wales, Australia
  • Kanishka Pushpitha
    Clinical Medicine, Macquarie University, Sydney, New South Wales, Australia
  • yogita dheer
    Clinical Medicine, Macquarie University, Sydney, New South Wales, Australia
  • Stuart L Graham
    Clinical Medicine, Macquarie University, Sydney, New South Wales, Australia
    Save Sight Institute, University of Sydney, Sydney, New South Wales, Australia
  • Footnotes
    Commercial Relationships   mojdeh abbasi, None; Vivek Kumar Gupta, None; Nitin Chitranshi, None; Kanishka Pushpitha, None; yogita dheer, None; Stuart Graham, None
  • Footnotes
    Support  The Skipper Postgraduate and Early Career Researcher Travel Award, Macquarie University, Sydney, Australia
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 2254. doi:
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      mojdeh abbasi, Vivek Kumar Gupta, Nitin Chitranshi, Kanishka Pushpitha, yogita dheer, Stuart L Graham; Inner retinal injury induced by acute elevation of IOP is mediated independently of Shp2 silencing effects. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2254.

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

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Abstract

Purpose : Growing evidence indicates that brain-derived neurotrophic factor (BDNF) and its receptor, TrkB play a critical role in protecting retinal ganglion cells (RGC). Our studies have recently established that SH2-domain-containing tyrosine phosphatase2 (Shp2) exerts a negative effect on the BDNF/TrkB signalling. Our data suggest that this effect is mediated through Caveolin-1 (Cav-1) protein, a gene locus recently implicated in glaucoma. We previously showed that Shp2 suppression could impart partial protection to the retina against damage in chronic glaucoma. Here we examined the consequence of Shp2 downregulation in normal and Cav-1 deficient mice under acute elevation of intraocular pressure (IOP).

Methods : n=32 mice were induced by acute ocular hypertension (60 mmHg) through connecting their eyes to a 33-gauge needle linked to an external saline reservoir for 1 hour and sacrificed after 2 weeks. Using adeno-associated virus (AAV) constructs containing Shp2 shRNA, Shp2 was genetically knocked down in n=16 of mice 10 days prior to inducing the acute IOP. Inner retinal function was assessed through positive scotopic threshold response (pSTR) recordings while TUNEL assay and Brn3a immunofluorescence staining was used to evaluate apoptotic changes and ganglion cell layer alterations respectively.

Results : The retinas in both groups exposed to acutely elevated IOP showed lower pSTR amplitudes compared to their respective control fellow eye, although this relative loss was greater in WT retinas (WT: p<0.001, Cav-1-/-: p<0.05). Shp2 silencing only conferred marginal protection to the retina in the acute model of IOP elevation (13%±4.60 and 8%±10.71 respectively) in contrast to previously reported findings in the chronic model. High IOP resulted in apoptotic activation in the retina and reduced Shp2 expression did not rescue the retinas under these conditions (27%±22.78; 13%±20.91). A significant loss of Brn3a positive RGCs was observed under acute IOP elevation (43.57%±3.42) but only improved to 38.81%±3.69 following Shp2 downregulation (p=0.13).

Conclusions : Shp2-mediated knockdown conferred only marginal protection in an acute ischemic model of experimental glaucoma. The beneficial effect of Shp2 downregulation on BDNF/TrkB signaling seen in chronic models is not seen in acutely increased IOP and this is regardless of Cav-1 status, probably due to other mechanisms of damage in this model.

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

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