FGF23 is synthesised locally by renal tubules and activates injury-primed fibroblasts

• Published in: Scientific reports Vol. 7; no. 1; pp. 3345 - 14
• Main Authors: Smith, Edward R., Tan, Sven-Jean, Holt, Stephen G., Hewitson, Tim D.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.06.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/21; 13/31; 13/51; 13/89; 13/95; 14; 14/19; 38/77; 42/109; 631/80/304; 64; 64/60; 692/4022/1585/3182; 82/80; Animals; Cells, Cultured; Fibroblast growth factor 23; Fibroblast Growth Factors - metabolism; Fibroblasts; Fibroblasts - metabolism; Fibrosis; HEK293 Cells; Humanities and Social Sciences; Humans; Kidney Tubules - metabolism; Kidneys; Klotho protein; Male; Mice; Mice, Inbred C57BL; multidisciplinary; Proprotein convertases; Rats; Rats, Sprague-Dawley; Renal Insufficiency, Chronic - metabolism; Renal tubules; Rodents; Science; Science (multidisciplinary); Signal Transduction; Ureter
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-02709-w

In kidney disease, higher circulating levels of the mineral-regulating hormone fibroblast growth factor (FGF)-23 are predictive of disease progression but direct pathogenic effects on the kidney are unknown. We sought evidence of local renal synthesis in response to unilateral ureteric obstruction in the mouse, and pro-fibrotic actions of FGF23 on the fibroblast in vitro . Acute tubulointerstitial injury due to unilateral ureteric obstruction stimulated renal FGF23 synthesis by tubules, and downregulated inactivating proprotein convertases, without effects on systemic mineral metabolism. In vitro , FGF23 had divergent effects on fibroblast activation in cells derived from normal and obstructed kidneys. While FGF23 failed to stimulate fibrogenesis in normal fibroblasts, in those primed by injury, FGF23 induced pro-fibrotic signalling cascades via activation of TGF-β pathways. Effects were independent of α-klotho. Tubule-derived FGF23 may amplify myofibroblast activation in acute renal injury, and might provide a novel therapeutic target in renal fibrosis.