Figure 6.

Crosstalk between RAAS and FGF-23 pathways. A new schema of hemodynamic regulation suggests actions of Ang II to stimulate FGF-23 in bone (afferent limb), leading to additive renal effects with Ang II (efferent limb) to increase blood pressure and cardiomegaly. In this model, FGF-23 effects are mediated by activation of FGFR/α-Klotho complexes, whereas Ang II activates AT1 receptors in renal tubules to enhance sodium transport, and to suppress α-Klotho. The resulting positive sodium balance leads to increased blood pressure and the reduced levels of soluble Klotho (s-Kl) may enhance cardiotoxicity through s-Kl-dependent TRPC6 cardiac effects. In contrast, FGF-23 suppresses, whereas Ang II stimulates Ace2, making degradation of Ang II and formation of Ang 1–7 a possible point of differential control. FGF-23 also suppresses 1,25(OH)₂D synthesis, an effect predicted to increase renin production by the kidney. This novel feed-forward endocrine pathway may contribute to the association between elevated FGF-23 and adverse cardiovascular outcomes. In addition, Ang II upregulates FGF-23 and α-Klotho expression the heart and macrophages to possible reconstitute FGFR/α-Klotho signaling leading to paracrine effects of FGF-23 to induce cardiac hypertrophy and stimulate inflammation.