Abstract
Purpose :
The retinoid X receptor (RXR) governs gene transcriptional programs for lipid metabolism which can be dysregulated in diabetic retinopathy (DR). Previously we demonstrated downregulation of RXR expression in both human and mouse diabetic retinas. The current study aims to validate RXR's role and utilize RXR-based therapy for therapeutic intervention in DR progression.
Methods :
Models of Type 1 diabetes induced by streptozotocin (STZ) injection in C57BL6 mice and Type 2 diabetes using db/db mice were employed in the study. Intravitreal administration of AAV2-RXR was used to overexpress RXR in the retina of diabetic mice. Additionally, the RXR agonist, UAB126 rexinoid, was delivered to diabetic retinas either systemically through gavage or topically using a pre-designed eyedrop formulation. To confirm that UAB126's crossed the blood-retinal barrier, LC-MS was used to measure levels. Control and RXR-treated mice underwent analysis of BGL and insulin levels, retinal function tests, histological evaluations, and protein and RNA analyses. Retinal explants from C57BL6 mice were cultured in media containing either mannitol (19 mM; control) or D-glucose (34 mM; high glucose) to simulate a hyperglycemic environment. The ex vivo explants were treated with 100 nM UAB126.
Results :
RXR overexpression prevented a 50% decline in scotopic ERG a- and b-wave amplitudes in diabetic mice two months post-injection of AAV2-RXR. Both systemic and eye drop applications successfully delivered UAB126 to the retina. Systemic delivery of UAB126 significantly reduced BGL by 40% without affecting insulin levels in T1D mice and was associated with a 50% increase in p-AMPK levels and a 40% improvement in both scotopic ERG a- and b-amplitudes. Retinal extracts cultured in a high glucose medium showed a decline in Rxrα, Pparα, and Lxrα mRNA, which was reversed upon treatment with UAB126. Additionally, topical application of UAB126 in db/db mice for two weeks demonstrated an increase in the expression of Elovl4, Acly, Fasn, Scd1, and Acc1 genes responsible for lipid metabolism.
Conclusions :
RXR-based therapy demonstrated efficacy in the diabetic retina. When given systemically, UAB126 also reduced hyperglycemia. Retinal delivery restored expression of genes responsible for lipid metabolism, thus delaying DR progression. Future experiments should validate additional mechanisms that mediate the therapeutic efficacy of RXR agonists including their anti-inflammatory effects.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.