Abstract
Chronic kidney disease (CKD) is a major global health problem, with substantial associated morbidity and mortality. Fibrosis is the final common pathway of organ damage in CKD, so understanding how this arises during kidney injury is critical for building a holistic picture of the pathogenesis. Here, using gene expression data, intravital microscopy in mice and realistic cell models, we uncover evidence of a signaling pathway linking tubular pyrimidine metabolism and injury-evoked extracellular uridine diphosphate (UDP) release to activation of the P2Y6 receptor (P2Y6R) in surrounding fibroblasts. We show that P2Y6R activation triggers intracellular calcium rises, which stimulate fibroblast proliferation, migration, and conversion towards a myofibroblast phenotype. Conversely, genetic knockout or pharmacological blockade of the P2Y6R reduces fibrosis in mice with CKD. Thus, we reveal that pyrimidinergic calcium signaling couples fibroblast responses to changes in tubular metabolism in disease states, and represents a potential new target for therapeutic intervention.
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All data relevant to judge and interpret this study were included in the paper and its accompanying Supplementary Information and Source data Files. The snRNA-seq datasets used in this study were previously published and are publicly available in the Gene Expression Omnibus under accession codes GSE151167, GSE139107, and GSE218376: www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE151167, www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE139107, www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE218376 Source data are provided with this paper.
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Acknowledgements
The authors acknowledge support from The Center for Microscopy and Image Analysis, University of Zurich. This work was supported by the Swiss National Centre for Competence in Research (NCCR) Kidney Control of Homeostasis (Grant ID: 183774) and a Swiss National Science Foundation project grant (310030_184688). Work in the P.E.C. Laboratory is supported by the Balli and Gianella foundations and the Ente Ospedaliero Cantonale Junior Grant.
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Conceptualization: A.M.H. Experimentation: A.F., N.J., S.K., M.K., I.S., and B.R. Data analysis: A.F., N.J., A.R., P.C., and B.R. Funding acquisition: A.M.H. Project supervision: A.M.H. Writing—original draft: A.F. and A.M.H. Writing—review and editing: all authors.
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Figurek, A., Jankovic, N., Kollar, S. et al. Pyrimidinergic calcium signaling links tubular metabolism to fibrosis in kidney disease. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69602-x
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DOI: https://doi.org/10.1038/s41467-026-69602-x
