FGF23 expression is stimulated in transgenic α-Klotho longevity mouse model

Observations in transgenic alpha-Klotho (Kl) mice (Kl(Tg)) defined the antiaging role of soluble Klotho (sKL(130)). A genetic translocation that elevates sKL levels in humans is paradoxically associated with increased circulating fibroblast growth factor 23 (FGF23) levels and the potential of both membrane KL (mKL(135)) and sKL(130) to act as coreceptors for FGF23 activation of fibroblast growth factor receptors (FGFRs). Neither FGF23 expression nor the contributions of FGF23, mKL(135), and sKL(130) codependent and independent functions have been investigated in Kl(Tg) mice. In the current study, we examined the effects of Kl overexpression on FGF23 levels and functions in Kl(Tg) mice. We found that mKL(135) but not sKL(130) stimulated FGF23 expression in osteoblasts, leading to elevated Fgf23 bone expression and circulating levels in KlTg mice. Elevated FGF23 suppressed 1,25(OH)(2)D and parathyroid hormone levels but did not cause hypophosphatemic rickets in Kl(Tg) mice. Kl(Tg) mice developed low aldosterone-associated hypertension but not left ventricular hypertrophy. Mechanistically, we found that mKL(135) and sKL(130) are essential cofactors for FGF23-mediated ERK activation but that they inhibited FGF23 stimulation of PLC-gamma and PI3K/AKT signaling. Thus, increased longevity in Kl(Tg) mice occurs in the presence of excess FGF23 that interacts with mKL and sKL to bias FGFR pathways.