Figure 3.

FGF23 signaling in the kidney. In kidney proximal tubules, circulating FGF23 binds to FGFR1-Klotho complexes at the basolateral membrane, and activates the MAPK signaling cascade involving ERK1/2. This signaling leads to the internalization and degradation of NPT2A/C and the decrease of urinary phosphate reabsorption promoting phosphate wasting. In the proximal tubule, FGF23 signaling induces downstream mechanisms which suppress the transcription of the vitamin D 1α-hydroxylase (CYP27B1) and increases the transcription of the vitamin D 24-hydroxylase (CYP24A1); both events work in concert to limit the conversion of 25D to 1,25D as well as degrading 1,25D into inactive metabolites. In the kidney distal tubule, circulating FGF23 binds to the FGFR-Klotho receptor complex at the basolateral membrane, and activates the MAPK/pERK/EGR1 pathway as well as cascade signaling for ERK1/2, SGK1, and the WNK4 complex via their phosphorylation. Activation of WNK signaling increases the expression of TRPV5 and NCC at the apical membrane promoting the reabsorption of calcium and sodium, respectively.