June 2013
Volume 54, Issue 15
Free
ARVO Annual Meeting Abstract  |   June 2013
Modulating inflammation in retina through targeting of GPR109A: Novel implications for therapeutic management of diabetic retinopathy
Author Affiliations & Notes
  • Deeksha Gambhir
    Biochemistry and Molecular Biology, Georgia Health Sciences University, Augusta, GA
  • Rajalakshmi Veeranan-Karmegam
    Biochemistry and Molecular Biology, Georgia Health Sciences University, Augusta, GA
  • Amany Tawfik
    Cellular Biology and Anatomy, Georgia Health Sciences University, Augusta, GA
  • Sylvia Smith
    Cellular Biology and Anatomy, Georgia Health Sciences University, Augusta, GA
    Ophthalmology, Georgia Health Sciences University, Augusta, GA
  • Vadivel Ganapathy
    Biochemistry and Molecular Biology, Georgia Health Sciences University, Augusta, GA
  • Pamela Martin
    Biochemistry and Molecular Biology, Georgia Health Sciences University, Augusta, GA
    Ophthalmology, Georgia Health Sciences University, Augusta, GA
  • Footnotes
    Commercial Relationships Deeksha Gambhir, None; Rajalakshmi Veeranan-Karmegam, None; Amany Tawfik, None; Sylvia Smith, None; Vadivel Ganapathy, None; Pamela Martin, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 1772. doi:
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      Deeksha Gambhir, Rajalakshmi Veeranan-Karmegam, Amany Tawfik, Sylvia Smith, Vadivel Ganapathy, Pamela Martin; Modulating inflammation in retina through targeting of GPR109A: Novel implications for therapeutic management of diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1772.

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

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Abstract

Purpose: Inflammation is a common pathologic factor in degenerative diseases of the retina. Identifying novel strategies for its limitation is therefore critically important and broadly relevant clinically. We reported recently on GPR109A expression in retina; however, little is known regarding the functional relevance of the receptor in this tissue. We have compelling preliminary data demonstrating an anti-inflammatory role for GPR109A in vitro. Our goal here was to validate this finding and hence, the potential of the receptor as a therapeutic target for combating retinal inflammation, in vivo.

Methods: Endotoxin-induced uveitis (EIU) and streptozotocin-induced diabetes (STZ-DBs) were used as models of acute and chronic retinal inflammation, respectively, in wildtype (Gpr109a+/+) and knockout (Gpr109a-/-) mice . The GPR109A-specific ligands, nicotinic acid (NA), β-hydroxybutyrate (β-HB), or PBS (controls) were administered (i.p.) to animals with/without EIU. Molecular markers of inflammation (ICAM-1, TNF-α, IL-1β, Ccl2, and IL-6) were evaluated in EIU and/or STZ-DB animals by qPCR and/or ELISA assay. Leukostasis assay was also performed. VEGF and endoglin (CD105) expression was evaluated in normal and STZ-DB wildtype and knockout retinas via qPCR and/or immunofluorescence.

Results: NA and β-HB treatment inhibited significantly EIU-associated increases in pro-inflammatory cytokine expression and leukocyte adherence in inner retinal blood vessels. Absence of GPR109A (Gpr109a-/-) was associated with robust increases in retinal pro-inflammatory cytokine expression that were exacerbated further by diabetes. VEGF and CD105 expression was upregulated in normal and STZ-DB Gpr109a-/- retinas as early as 2 weeks post-onset diabetes. VEGF was similarly upregulated in STZ-DB wildtype retinas, but to a much lesser extent than in STZ-DB knockouts. CD105 expression was minimal in wildtype animals even in the presence of STZ-DBs.

Conclusions: GPR109A is a key regulator of retinal inflammation under normal and pathologic conditions. Targeting of GPR109A may be useful in the treatment/prevention of degenerative retinal diseases in which inflammation is majorly involved (i.e., diabetic retinopathy).

Keywords: 557 inflammation • 499 diabetic retinopathy • 695 retinal degenerations: cell biology  
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