The Regulation Of Oxidative Stress On KLF4 And IL17RA In Age-related Macular Degeneration

Reactive oxygen species(ROS)accumulated during oxidative stress(OS)is a majordeleterious factor for cell structure and function.Retinal pigment epithelial(RPE)cells are a signal layer of pigmented cells between the retina photoreceptors and choroid.One of the physiological function of RPE is phagocytosis and degraded photoreceptor outer segments,the process producing and accumulating ROS in cell.Previous studies have revealed that OS promotes the development of inflammation.OS and inflammation play pivotal roles in RPE degeneration and pathogenesis of age-related macular degeneration,the leading cause of irreversible blindness in the elders.Interleukin17 signaling is a key signal pathway promoting inflammation.Previous studies have shown that IL17 RC,the receptor of IL17,highly expresses in AMD patients,and activates of IL17 signaling pathway promoting RPE injury and AMD occurrence.However,the regulatory mechanism of IL17 signaling pathway in oxidative stress is unknown.The in vitro OS model was established by treating human RPE cell line ARPE19 with glucose oxidase.The in vivo OS model was generated by intraperitoneal injection of sodium iodate into mice.The expression of IL17 receptors and the transcription factor KLF4 were determined by qRT-PCR and western blot analysis.The interaction between KLF4 and IL17 RA promoter was accessed by electronic mobility shifting assay and chromatin immunoprecipitation assay.To investigate the transactivity of KLF4 on IL17 RA,the expression of KLF4 was altered by overexpression or knockdown of KLF4 gene in RPE cells.Our results show that:(1)IL17RA was significantly upregulated in the presence of OS in RPE cells;(2)Il17RA upregulate the downstream inflammatory cytokines in the presence of OS in RPE cells;(3)The combination of KLF4 and IL17 RA promoter is enhanced in the presence of OS in RPE cells;(4)KLF4 was significantly upregulated in the presence of OS in RPE cells.Our study showed that KLF4 activates IL17 RA transcription upon OS exposure,contributing to the inflammatory response in RPE cells.The present work has revealed an unrecognized mechanism through which KLF4 regulates cytokine production,which may improve our understanding in eye diseases caused by RPE degeneration,such as AMD.