Effect of FGF23 on Transcription in WT mouse kidney samples

It is currently unclear whether elevated circulating fibroblast growth factor-23 (FGF23) causes maladaptive pathological effects in chronic kidney disease (CKD). In the wider study we analyzed the pathophysiological role of Fgf23 in 5/6-nephrectomy-induced CKD in mice. Using genetic loss-of-function together with acute FGF23 signaling inhibition models, we found that high circulating concentrations of intact FGF23 activate with-no-lysine kinase (WNK) signaling pathways in the kidney, contributing to renal sodium retention in CKD mice. A prospective study in CKD patients confirmed the association between serum intact FGF23 and renal WNK activation. Notably, the small molecule WNK signaling inhibitors closantel and WNK463 improved renal function in CKD mice. Furthermore, using RNA-Seq in FGF23-treated mice together with acute anti-FGF23 antibody therapy in CKD mice, we found that FGF23 potently stimulates pro-inflammatory signaling in renal epithelium. In conclusion, our study identified Fgf23 as a major disease-modulating factor in CKD, driving WNK and pro-inflammatory signaling pathways in the kidney.