FGFR1-phosphate sensing and crystal-induced gasdermin D signaling in neutrophils drive vascular calcification in CKD

Miyoshi-Harashima, A.; Nakazawa, D.; Shimizu, T.; Watanabe-Kusunoki, K.; Hattanda, F.; Nishio, S.; Shiratori-Aso, S.; Ueda, Y.; Kimura, M.; Kawamura, T.; Takenaka, S.; Kanda, M.; Masuda, S.; Nishibata, Y.; Tomaru, U.; Shingu, Y.; Wakasa, S.; Ishizu, A.; Atsumi, T.

doi:10.64898/2026.05.23.725305

bioRxiv · 10.64898/2026.05.23.725305

FGFR1-phosphate sensing and crystal-induced gasdermin D signaling in neutrophils drive vascular calcification in CKD

Miyoshi-Harashima, A.·Nakazawa, D.·Shimizu, T.·Watanabe-Kusunoki, K.·Hattanda, F.·Nishio, S.·Shiratori-Aso, S.·Ueda, Y.·Kimura, M.·Kawamura, T.·Takenaka, S.·Kanda, M.·Masuda, S.·Nishibata, Y.·Tomaru, U.·Shingu, Y.·Wakasa, S.·Ishizu, A.·Atsumi, T.

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Abstract

Chronic kidney disease (CKD) confers disproportionate cardiovascular risk. In non-dialysis CKD, calcification accumulates primarily within the intimal layer. Clinical studies indicate that intimal calcification correlates with hyperphosphatemia, yet the cellular and molecular pathways remain unclear. Given evidence that osteocytes sense phosphate via fibroblast growth factor receptor 1 (FGFR1), we hypothesized that FGFR1-expressing vascular immune cells, especially neutrophils, act as mediators linking high phosphate to plaque mineralization. In vitro, phosphate triggered FGFR1-dependent signaling in human and murine neutrophils, inducing neutrophil extracellular traps (NETs). Activated neutrophils promoted the depletion of Fetuin-A, a major inhibitor of calcium-phosphate complexation, creating a milieu permissive to mineral nucleation. Newly formed calcium-phosphate particles amplified NETs through gasdermin D (GSDMD), establishing a feed-forward loop that enhanced mineralization and endothelial injury in co-culture assays. Human arteriosclerotic plaques from CKD patients showed NETs markers co-localizing with calcified deposits. In vivo, pharmacological FGFR inhibition attenuated arterial intimal calcification and suppressed NET formation in CKD mice. These findings identify phosphate sensing via neutrophil FGFR1 and subsequent crystal-induced GSDMD signaling as drivers of intimal vascular calcification in CKD. Targeting phosphate-sensing pathways, NET formation, and neutrophil-driven mineralization may mitigate vascular calcification and reduce cardiovascular risk in CKD.

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Miyoshi-Harashima, A., Nakazawa, D., Shimizu, T., Watanabe-Kusunoki, K., Hattanda, F., Nishio, S., Shiratori-Aso, S., Ueda, Y., Kimura, M., Kawamura, T., Takenaka, S., Kanda, M., Masuda, S., Nishibata, Y., Tomaru, U., Shingu, Y., Wakasa, S., Ishizu, A., Atsumi, T.. 2026-05-26. FGFR1-phosphate sensing and crystal-induced gasdermin D signaling in neutrophils drive vascular calcification in CKD. https://doi.org/10.64898/2026.05.23.725305

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