Chronic kidney disease (CKD) leads to accumulation of uremic toxins, which contribute to cardiovascular disease (CVD) and mortality. Among these, fibroblast growth factor 23 (FGF-23), a bone-derived hormone, is associated with arterial stiffness, vascular calcification, and left ventricular hypertrophy. However, the mechanisms linking elevated FGF-23 levels to vascular alterations remain poorly understood. We hypothesized that FGF-23 modulates the expression of sulfated glycosaminoglycans (sGAGs) and hyaluronic acid (HA) in vascular cells. Rat vascular smooth muscle cells (VSMCs) and human endothelial cells (ECs) were treated with FGF-23 ± its co-receptor Klotho and analyzed using qPCR, Western blotting, Blyscan assay, Alcian blue staining, ELISA, and reporter assays. FGF-23 significantly increased sGAG (2.5-fold) and HA (1.6-fold) levels in VSMCs, and sGAG (50-fold) and HA (3.7-fold) levels in ECs. Klotho alone induced a ∼72-fold rise in sGAGs in ECs but had no effect in VSMCs. FGF-23 also upregulated GAG-specific gene expressions of carbohydrate sulfotransferase 1 and xylosyltransferase 2 ∼1.6-fold and increased HA-specific hyaluronan synthase-2 and -3 protein expression. These effects were mediated by ERK and NF-κB signaling. To evaluate biological relevance, we assessed calcium- and phosphate-induced calcification in VSMCs. FGF-23 significantly enhanced calcification by ∼65%, which paralleled elevated sGAG levels. Inhibition of GAG sulfation with NaClO3 significantly reduced sGAGs and prevented FGF-23-induced calcification. Similarly, the FGFR inhibitor AZD4547 abolished FGF-23-induced increases in sGAGs and calcification in both VSMCs and ECs. These findings indicate that FGF-23 modulates vascular GAG composition and promotes calcification, thereby contributing to pathological vascular remodeling in CKD.
Freise et al. (Mon,) studied this question.