Purchase this article with an account.
D. Gambhir, S. B. Smith, V. Ganapathy, P. M. Martin; Upregulation of GPR109A, a Novel Receptor for β-Hydroxybutyrate, in Diabetic Retina. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5615.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
GPR109A is a G-protein coupled receptor for β-hydroxybutyrate (β-HB), an important energy source for neurons under various physiologic and pathologic conditions. Under normal conditions, endogenous β-HB levels are too low to significantly impact GPR109A activity. However, the circulating levels of β-HB increase several-fold in uncontrolled diabetes, suggesting that activation of GPR109A with β-HB may be of relevance to diabetes. We reported previously that GPR109A is expressed in normal retina. In the present study, we asked whether GPR109A expression in retina is altered in diabetes; a highly relevant question, given that diabetic retinopathy is a serious complication associated with diabetes.
Streptozotocin-induced diabetic mice and Ins2Akita/+ mice were used as models of type 1 diabetes in these studies. Age-matched, non-diabetic animals served as controls. RT-PCR and immunohistochemical techniques were used to analyze retinal GPR109A expression in early (4-6 weeks), moderate (8-12 weeks) and advanced (>14 weeks) diabetes. Bioluminescence resonance energy transfer (BRET) technique was used to study functional interaction of β-HB with GPR109A in vitro.
In early/moderate stage diabetic retina, GPR109A protein was restricted primarily to the basolateral membrane of RPE, a pattern of expression consistent with that observed in control retinas. Additionally, there was no detectable change in GPR109A mRNA expression. Advanced diabetes, however, was associated with a significant increase in GPR109A mRNA and protein expression in RPE. Additionally, positive signals for GPR109A protein were detectable in neural retina, likely associated with labeling of retinal blood vessels. All results were comparable between the two animal models. BRET assay confirmed activation of GPR109A by β-HB.
This is the first report on GPR109A expression in diabetic retina. GPR109A expression in retina is not altered in short-term diabetes, but is significantly upregulated with prolonged diabetes. Future studies will determine whether this receptor has any role in the biology of the retina and in the pathogenesis of diabetic retinopathy.
This PDF is available to Subscribers Only