Pyrimidinergic calcium signaling links tubular metabolism to fibrosis in kidney disease

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.