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Osmoregulation is essential for organisms to adapt to the exterior environment and plays an important role in embryonic organogenesis. Tubular organ formation usually involves a hyperosmotic lumen environment. The mechanisms of how the cells respond and regulate lumen formation remain largely unknown. Here, we reported that the nuclear factor of activated T cells-5 (<i>NFAT5</i>), the only transcription factor in the <i>NFAT</i> family involved in the cellular responses to hypertonic stress, regulated notochord lumen formation in chordate <i>Ciona</i>. <i>Ciona NFAT5</i> (<i>Ci</i>-<i>NFAT5</i>) was expressed in notochord, and its expression level increased during notochord lumen formation and expansion. Knockout and expression of the dominant negative of <i>NFAT5</i> in <i>Ciona</i> embryos resulted in the failure of notochord lumen expansion. We further demonstrated that the <i>Ci</i>-NFAT5 transferred from the cytoplasm into nuclei in HeLa cells under the hyperosmotic medium, indicating <i>Ci-NFAT5</i> can respond the hypertonicity. To reveal the underly mechanisms, we predicted potential downstream genes of <i>Ci-NFAT5</i> and further validated <i>Ci-NFAT5-</i>interacted genes by the luciferase assay. The results showed that <i>Ci-</i>NFAT5 promoted <i>SLC26A6</i> expression. Furthermore, expression of a transport inactivity mutant of <i>SLC26A6</i> (L421P) in notochord led to the failure of lumen expansion, phenocopying that of <i>Ci-NFAT5</i> knockout. These results suggest that <i>Ci</i>-<i>NFAT5</i> regulates notochord lumen expansion via the SLC26A6 axis. Taken together, our results reveal that the chordate <i>NFAT5</i> responds to hypertonic stress and regulates lumen osmotic pressure via an ion channel pathway on luminal organ formation.