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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)
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.
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.
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.
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).
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