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Translational studies have shown that hyperphosphatemia contributes to CKD-associated inflammation and injury in various tissues, including the kidney, heart, liver, and parathyroid gland. Mechanisms underlying pathologic actions of elevated phosphate on cells are not well understood but seem to involve uptake of phosphate through sodium phosphate cotransporters and phosphate-induced signaling via FGFR1 (fibroblast growth factor receptor 1). Clinical studies indicate patients with CKD are more likely to develop inflammatory and restrictive lung diseases, such as fibrotic interstitial lung diseases, and here we aimed to determine whether hyperphosphatemia can cause lung injury. We found that a mouse model of CKD and hyperphosphatemia, induced by an adenine-rich diet, develops lung fibrosis and inflammation. Elevation of systemic phosphate concentration by administration of a high-phosphate diet in a mouse model of primary lung inflammation and fibrosis, induced by bleomycin, exacerbated lung injury in the absence of kidney damage. Our in vitro studies identified increases of proinflammatory cytokines in human lung fibroblasts exposed to phosphate elevations. Phosphate activated ERK 1\/2 (extracellular signal-related kinase 1\/2) and PKB\/AKT (protein kinase B) signaling, and pharmacological inhibition of ERK, AKT, FGFR1, or sodium phosphate cotransporters prevented phosphate-induced proinflammatory cytokine upregulation. In addition, inhibition of FGFR1 or sodium phosphate cotransporters decreased the phosphate-induced activation of ERK and AKT. Our study suggests that phosphate can directly target lung fibroblasts and induce an inflammatory response and that hyperphosphatemia in CKD and non-CKD models contributes to lung injury. Phosphate-lowering strategies might protect from CKD-associated lung injury.<\/jats:p>","DOI":"10.1165\/rcmb.2024-0008oc","type":"journal-article","created":{"date-parts":[[2024,8,1]],"date-time":"2024-08-01T15:49:01Z","timestamp":1722527341000},"page":"659-676","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":5,"title":["Chronic Kidney Disease\u2013associated Lung Injury Is Mediated by Phosphate-induced MAPK\/AKT Signaling"],"prefix":"10.1093","volume":"71","author":[{"given":"Seth","family":"Bollenbecker","sequence":"first","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meghan June","family":"Hirsch","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma 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