Kaempferol protects against photooxidative stress-triggered photoreceptor degeneration in part by inhibiting Rac1 activation.

BACKGROUND: Photoreceptor degeneration directly leads to irreversible vision impairment. Effective treatments attenuating photoreceptor degeneration remain to be developed. Activation of Rac1 mediates photooxidative stress-induced photoreceptor degeneration. Kaempferol (KAE), a flavonoid with antioxidant activities, is putatively effective at suppressing Rac1 activation. However, it is unknown if KAE is effective at mitigating photooxidative stress and protecting against photoreceptor degeneration. PURPOSE: This study aimed to investigate the pharmacological implications and mechanisms of KAE in protecting against photooxidative stress-induced photoreceptor degeneration. STUDY DESIGN: In vivo experiments were conducted in light-exposed BALB/c mice to investigate the pharmacological impact of KAE on photooxidative stress-induced photoreceptor degeneration. In silico analyses and in vitro experiments were performed to explore the possibility that KAE may directly interact with human RAC1 and suppress the activation of RAC1. METHODS: Non-invasive optical coherence tomography, electroretinography, RNA sequencing, real-time qPCR, immunohistochemistry, TUNEL, in situ assessment of reactive oxygen species (ROS) and Rac1 activation assay were conducted to characterize the protective effects of KAE against photooxidative stress-induced photoreceptor degeneration and evaluate its impact on Rac1 activity in the retina. Molecular docking, molecular dynamics simulations, and surface plasmon resonance were performed to address if KAE directly interacts with human RAC1. Pull-down assay was conducted to validate if KAE suppresses RAC1 activation. RESULTS: KAE protected against the structural impairment of the photoreceptors, preserved the retinal function, and maintained the retinal transcriptome in the light-exposed mice. Moreover, KAE suppressed light-augmented Rac1 activity in the retina and overproduction of ROS in the photoreceptors. Furthermore, KAE directly interacted with human RAC1 and suppressed the activation of RAC1. CONCLUSION: The current study demonstrates for the first time that KAE is effective at protecting against photooxidative stress-mediated photoreceptor degeneration, which may in part implicate inhibition of Rac1 activation. Thus, the findings here shed new light on the pharmacological implications and mechanisms of KAE in mitigating photoreceptor degeneration.