Abstract
Purpose :
Photoreceptor contribution to DR pathology relates to hyperglycemia-induced generation of superoxide by mitochondria followed by upregulation of inflammatory markers. Energy demand, oxygen consumption, and superoxide generation are greater in darkness than in light. Partial activation of phototransduction in the dark-adapted diabetic retina lessens oxygen consumption and may reduce superoxide generation. Apo-opsin with no visual chromophore can activate phototransduction in the dark. Partial reduction in 11-cis-retinal in the dark-adapted diabetic retina may yield partial activation of phototransduction. RBP4 antagonists are known to partially reduce levels of 11-cis-retinal. Efficacy of advanced RBP4 antagonists was evaluated in three DR models
Methods :
Transgenic mice with adipocyte-specific overexpressing of human RBP4 were used to study the effects of compound treatment on retinal changes induced by exposure to high-fat diet. C57BL/6J mice made diabetic with 5 sequential injections of medium-dose STZ were used to assess the effect of treatment on vascular leakage, capillary degeneration and pericyte loss after 8 months of treatment. C57BL/6J mice with hyperglycemia induced by a single high dose of STZ were used to evaluate the effect of compounds on vascular leakage and upregulation of inflammatory markers following 8 days of compound administration. Rhodopsin levels were spectrophotometrically measured in retinal extracts. Visual cycle retinoids were assessed with HPLC. RBP4 levels were measured with ELISA.
Results :
Compound administration induced a significant 80% reduction in the concentration of serum RBP4 which translated to a 30-50% reduction in visual cycle retinoids (including 11-cis-retinal). To a lesser extent, concentration of rhodopsin was also reduced in response to compound treatment. Vascular permeability and pericyte loss were attenuated in the diabetes model as a result of compound dosing. Compound administration partially normalized upregulation of pro-inflammatory markers in the diabetic mouse retina.
Conclusions :
As a result of pharmacological modulation of the visual cycle by oral administration of RBP4 antagonists, normalization of the phenotype was seen in mouse models of diabetic retinopathy. Potential mechanisms for this beneficial effect may involve activation of phototransduction in the dark-adapted retina which would reduce energy demands in photoreceptor cells
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.