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Blue light, a high-energy component of the natural light spectrum, has become an increasing concern due to widespread exposure from 3C electronic devices. While blue light plays an essential role in circadian rhythm regulation, prolonged exposure has been associated with retinal dysfunction and vascular impairment. However, its direct impact on retinal endothelial integrity remains largely unexplored.
The inner blood-retinal barrier (iBRB), primarily formed by endothelial cells with well-structured tight junctions, is crucial for maintaining retinal homeostasis. Our study demonstrates that blue light exposure rapidly degrades endothelial claudin-5 (CLDN5), a key tight junction protein, through the activation of A Disintegrin And Metalloprotease 17 (ADAM17), even under non-cytotoxic lighting conditions. This degradation compromises tight junction integrity, increases paracellular permeability, and induces iBRB leakage, leading to electrophysiological impairments such as attenuated electroretinogram (ERG) and oscillatory potentials in mice.
We further identified that ADAM17 is normally sequestered by GNAZ (G Protein Subunit Alpha Z), an inhibitory Gα protein enriched in the retina. However, blue light disrupts this interaction, resulting in ADAM17 hyperactivation and CLDN5 degradation. Additionally, PKCα was identified as a key mediator of blue light-induced endothelial dysfunction, as blue light significantly increased PKCα phosphorylation and ADAM17 activation, exacerbating CLDN5 degradation. Pretreatment with PKC inhibitors and the natural compound LB53 effectively suppressed PKCα and ADAM17 activation, preventing tight junction disruption.
Moreover, blue light exposure appears to trigger proinflammatory responses. Our findings suggest that retinal endothelial cells may detect blue light through specialized receptors and signaling adaptors, activating a GNAZ-dependent inflammatory pathway. Given that GNAZ functions as a circadian-responsive protein, it may also play a role in light perception and retinal adaptation to environmental lighting conditions.