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

Kaempferol, a flavonoid with antioxidant activities, is putatively effective at suppressing Rac1 activation. However, it is unknown if kaempferol is effective at mitigating photooxidative stress and protecting against photoreceptor degeneration. Purpose: This study aimed to investigate the pharmacological implications and mechanisms of kaempferol 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 kaempferol on photooxidative stress-induced photoreceptor degeneration. In silico analyses and in vitro experiments were performed to explore the possibility that kaempferol may directly interact with human RAC1 and suppress the activation of RAC1.

Methods

Non-invasive optical coherence tomography and electroretinography as well as RNA sequencing were conducted to characterize the protective effects of kaempferol against photooxidative stress-induced photoreceptor degeneration. Molecular docking, molecular dynamics simulations, and surface plasmon resonance were performed to address if kaempferol directly interacts with human RAC1. Pulldown assay was conducted to validate if kaempferol suppresses RAC1 activation.

Results: Kaempferol protected against the structural impairment of the photoreceptors, preserved the retinal function, and maintained the retinal transcriptome in the lightexposed mice. Moreover, kaempferol suppressed light-augmented Rac1 activity in the retina and overproduction of reactive oxygen species in the photoreceptors. Furthermore, kaempferol directly interacted with human RAC1 and suppressed the activation of RAC1.

Conclusion: The current study demonstrates for the first time that kaempferol is effective at protecting against photooxidative stress-mediated photoreceptor degeneration, which may in part implicate targeted inhibition of Rac1. Thus, the findings here shed new light on the pharmacological implications and mechanisms of kaempferol in mitigating photoreceptor degeneration.