The present study demonstrates that (i) AQP5 knockout can lead to primary dry eye development in mice (AQP5–/– mice have a stable dry eye phenotype since birth) and this phenotype may be produced by altering the structure of lacrimal glands, (ii) circRNA levels are significantly altered in the lacrimal glands of AQP5–/– mice, and (iii) the interactions of the circRNA–miRNA–mRNA network associated with phagosomes may regulate the expression of AQP5 involved in the pathogenesis of dry eye. Here, AQP5 is linked to Keratoconjunctivitis sicca.