Retinal pigment epithelial (RPE) cells increase in size and multinucleate during aging. We have shown using human and mouse cell lines that oxidised photoreceptor outer segments (oxPOS)-induced cytokinesis failure is related to RPE cell multinucleation, although the underlying mechanism remains unknown. This study investigated the role of the PKC pathway in oxPOS-induced RPE multinucleation using ARPE19 cells. oxPOS treatment promoted PKC activity and upregulated the mRNA expression of PKC α, δ, ζ, ι and μ. Inhibition of PKCα with Gӧ6976 resulted in a 33% reduction of multinucleate ARPE19 cells, whereas inhibition of PKCζ with Gӧ6983 led to a 50% reduction in multinucleate ARPE19 cells. Furthermore, oxPOS treatment induced a PKCζ-dependent upregulation of the Cdk inhibitor p27kip1, its inhibition using A2CE reduced oxPOS-induced ARPE19 multinucleation. Our results suggest that oxPOS-induced ARPE19 cytokinesis failure is, at least in part, due to the upregulation of p27kip1 through activating the PKC, particularly PKCζ pathway. Targeting the PKCζ-p27kip1 signalling axis may be a novel approach to restore RPE repair capacity during aging.
Keywords: aging; multinucleation; p27kip1; protein kinase C; retinal pigment epithelium.