Activation of aryl hydrocarbon receptor by azatyrosine-phenylbutyric hydroxamide inhibits progression of diabetic retinopathy mice.

Diabetic retinopathy (DR) is a severe consequence of long-term diabetes mellitus and may lead to vision loss. Retinal pigment epithelial (RPE) cells are a diverse group of retinal cells with varied metabolic and functional roles. In hypoxic conditions, RPE cells have been shown to produce angiogenic factors, such as vascular endothelial growth factor (VEGF), which is regulated by hypoxia-inducible factor 1-alpha (HIF1A). VEGF plays a crucial role in angiogenesis in DR. In the present study, we investigated whether azatyrosine-phenylbutyric hydroxamide (AZP) has therapeutic effect on DR therapy. In this study, we treated high glucose-activated human retinal pigment epithelial cells (ARPE-19) with and without AZP. The effector proteins were evaluated using western blotting. In the in vivo study, AZP was administered to the db/db mice as a DR animal model. Moreover, invasive imaging techniques such as optical coherence tomography (OCT), fundus photography, and fundus fluorescein angiography (FFA) were performed on the mice to assess DR progression. We found that treatment of AZP for 12 weeks reversed increasing DR retinal alterations in db/db mice, decreasing vascular density, retinal blood perfusion, retinal thickness, decreasing DR lesion, lipofuscin accumulation, HIF1A, VEGF, and inflammation factor expression. In addition, AZP treatment could activate the aryl hydrocarbon receptor AHR and reverse the high-glucose-induced HIF1A and VEGF in ARPE-19 cells and db/db mice. In conclusion, AZP activated AHR while inhibiting HIF1A and VEGF. This study indicates that AZP may be a promising therapeutic agent for treating DR.

The HDAC/HSP90 Inhibitor G570 Attenuated Blue Light-Induced Cell Migration in RPE Cells and Neovascularization in Mice through Decreased VEGF Production.

Age-related macular degeneration (AMD) occurs due to an abnormality of retinal pigment epithelium (RPE) cells that leads to gradual degeneration of the macula. Currently, AMD drug pipelines are endowed with limited options, and anti-VEGF agents stand as the dominantly employed therapy. Despite the proven efficacy of such agents, the evidenced side effects associated with their use underscore the need to elucidate other mechanisms involved and identify additional molecular targets for the sake of therapy improvement. The previous literature provided us with a solid rationale to preliminarily explore the potential of selective HDAC6 and HSP90 inhibitors to treat wet AMD. Rather than furnishing single-target agents (either HDAC6 or HSP90 inhibitor), this study recruited scaffolds endowed with the ability to concomitantly modulate both targets (HDAC6 and HSP90) for exploration. This plan was anticipated to accomplish the important goal of extracting amplified benefits via dual inhibition (HDAC6/HSP90) in wet AMD. As a result, G570 (indoline-based hydroxamate), a dual selective HDAC6-HSP90 inhibitor exerting its effects at micromolar concentrations, was pinpointed in the present endeavor to attenuate blue light-induced cell migration and retinal neovascularization by inhibiting VEGF production. In addition to the identification of a potential chemical tool (G570), the outcome of this study validates the candidate HDAC6-HSP90 as a compelling target for the development of futuristic therapeutics for wet AMD.