The adenosine A2A receptor antagonist KW6002 mitigates aldosterone-induced central serous chorioretinopathy in mice.

PURPOSE: Central serous chorioretinopathy (CSC), a prevalent disease characterized by choroidal vascular abnormalities, has extremely limited treatment options. This study investigates the effects of the selective adenosine A2A receptor (A2AR) antagonist KW6002 on choroidal vascular hyperpermeability and the blood-retinal barrier (BRB), and explores its therapeutic potential in experimental CSC.

METHODS: We examined A2AR expression in the retinal pigment epithelium (RPE)-choroid-sclera complex using quantitative real-time PCR (qPCR) and Western blotting (WB) in mice with an established aldosterone-induced acute CSC model. Before modeling and after model establishment, mice were administered 5 mg/kg KW6002 or a vehicle control via intraperitoneal injection. The retinal and choroidal thickness was assessed by optical coherence tomography (OCT) and hematoxylin-eosin (H&E) staining. We observed Müller cells activation, retinal microglia infiltration, and proinflammatory cytokine expression via immunofluorescence and qPCR. Next, we employed the effects of the A2AR antagonist KW6002 and genetic A2AR knockout (A2AR-KO) on BRB integrity using immunofluorescence and WB. Finally, to clarify how A2AR knockout confers therapeutic benefits in CSC, we assessed activation of the TNF-α/NF-κB-MMP-2/9 signaling pathway.

RESULTS: We found that A2AR signaling was significantly upregulated in the RPE-choroid-sclera complex in CSC models, and both A2AR antagonist KW6002 and A2AR-KO significantly inhibited the aldosterone-induced central retinal and choroidal pathologic thickening. Moreover, the KW6002 intervention decreased the activation of Müller cells and the proliferation of microglia, inhibited the secretion of proinflammatory cytokines (TNF-α, IL-6, and IL-1β), and ameliorated the retinal damage caused by aldosterone; in contrast, A2AR-KO resulted in significant upregulation of key tight junction proteins (ZO-1, Claudin-1, and Claudin-5). In summary, these results suggest that the protective effects may be correlated with the suppression of the TNF-α/NF-κB-MMP-2/9 signaling axis.

CONCLUSIONS: Our findings show that the A2AR antagonist KW6002 or A2AR-KO offers a protective effect in experimental CSC, reduces inflammation, and maintains the integrity of the BRB, which may be associated with the inhibition of the TNF-α/NF-κB-MMP-2/9 pathway. These findings present a new method for preventing and treating CSC, which will guide our future clinical strategy development.