Transcriptomics profiling reveals novel FGF23 targets in a Klotho-dependent and independent manner

Bone-derived hormone FGF23 and its co-receptor Klotho form a trimeric complex with FGFRs in target tissues, thus governing physiological FGF23 actions. Prolonged excess FGF23 levels in conditions like chronic kidney disease (CKD) may have cardiotoxic and inflammatory effects without requiring Klotho as a coreceptor. If and how FGF23 functions independently of Klotho is a topic of significant interest. Using in-vitro transcriptomics and further bioinformatics analysis, here we show that transient-low FGF23 treatment (~physiological) in presence of Klotho exhibit canonical signaling. However lack of Klotho led to almost no change in transcriptomics after FGF23 treatment. On the other hand, prolonged-excess FGF23 treatment (~pathological) revealed many novels targets of FGF23, which are also emerging biomarkers of CKD, suggesting FGF23 may activate these molecules in CKD. Remarkably, Klotho acted as a molecular switch by regulating, together with FGF23, the above-mentioned transcripts, thus determining the fate of FGF23 signaling. Overall, our findings provide proof-of-principle evidence for the Klotho dependent and independent FGF23 actions, which may hold great potential for investigating a precise role of FGF23 in health and disease. HEK293 and stable Klotho transfected HEK293-Kl were treated with low (0.5nM) and high FGF23 (10nM) for 1 h and 24h respectively. RNA was isolated and and samples were sequenced commercially at Novogene