GPR109A as an anti-inflammatory receptor in retinal pigment epithelial cells and its relevance to diabetic retinopathy.

Deeksha Gambhir, Sudha Ananth, Rajalakshmi Veeranan-Karmegam, Selvakumar Elangovan, Shanterian Hester, Eric Jennings, Stefan Offermanns, Julian J Nussbaum, Sylvia B Smith, Muthusamy Thangaraju, Vadivel Ganapathy, Pamela Moore Martin

Research output: Contribution to journalArticle

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Abstract

Retinal pigment epithelium (RPE) expresses GPR109A, a receptor for the vitamin niacin and the ketone body β-hydroxybutyrate (β-HB). Because diabetes results in elevated levels of β-HB, here we studied expression of the receptor in diabetic retina. We also investigated its functional relevance in RPE. Retinal expression of GPR109A in diabetic mice and postmortem human eyes was evaluated by quantitative PCR (qPCR). ARPE-19 cells and primary wild-type and Gpr109a(-/-) mouse RPE cells were exposed to TNF-α in the presence or absence of niacin or β-HB, followed by analysis of IL-6 and Ccl2 expression via real-time qPCR and ELISA. GPR109A expression was increased in diabetic mouse and human retina. TNF-α increased the expression and secretion of IL-6 and Ccl2 in ARPE-19 cells. Niacin and β-HB suppressed these effects, implicating GPR109A as the target responsible for mediation of the observed effects. Primary RPE cells from wild-type mice behaved similarly. In contrast, GPR109A ligands failed to suppress TNF-α-induced expression and secretion of IL-6 and Ccl2 in primary RPE cells from Gpr109a(-/-) mice, confirming that the observed anti-inflammatory effects were mediated specifically by Gpr109a. GPR109A plays an anti-inflammatory role in RPE and its expression is upregulated in diabetes. Inflammation is a key causative factor in the pathogenesis of diabetic retinopathy. We speculate that the increased expression of GPR109A and elevation of its ligand β-HB in diabetes are mechanisms by which the tissue attempts to fight inflammation in this disease. Pharmacological activation of GPR109A may therefore have therapeutic potential in clinical management of diabetic retinopathy.

Original languageEnglish (US)
Pages (from-to)2208-2217
Number of pages10
JournalInvestigative ophthalmology & visual science
Volume53
Issue number4
DOIs
StatePublished - Jan 1 2012
Externally publishedYes

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Retinal Pigments
Retinal Pigment Epithelium
Diabetic Retinopathy
Anti-Inflammatory Agents
Epithelial Cells
Niacin
Interleukin-6
Retina
Hydroxybutyrates
Ligands
Inflammation
Ketone Bodies
Vitamins
Real-Time Polymerase Chain Reaction
Enzyme-Linked Immunosorbent Assay
Pharmacology
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

GPR109A as an anti-inflammatory receptor in retinal pigment epithelial cells and its relevance to diabetic retinopathy. / Gambhir, Deeksha; Ananth, Sudha; Veeranan-Karmegam, Rajalakshmi; Elangovan, Selvakumar; Hester, Shanterian; Jennings, Eric; Offermanns, Stefan; Nussbaum, Julian J; Smith, Sylvia B; Thangaraju, Muthusamy; Ganapathy, Vadivel; Martin, Pamela Moore.

In: Investigative ophthalmology & visual science, Vol. 53, No. 4, 01.01.2012, p. 2208-2217.

Research output: Contribution to journalArticle

Gambhir, Deeksha ; Ananth, Sudha ; Veeranan-Karmegam, Rajalakshmi ; Elangovan, Selvakumar ; Hester, Shanterian ; Jennings, Eric ; Offermanns, Stefan ; Nussbaum, Julian J ; Smith, Sylvia B ; Thangaraju, Muthusamy ; Ganapathy, Vadivel ; Martin, Pamela Moore. / GPR109A as an anti-inflammatory receptor in retinal pigment epithelial cells and its relevance to diabetic retinopathy. In: Investigative ophthalmology & visual science. 2012 ; Vol. 53, No. 4. pp. 2208-2217.
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