Abstract
Fibroblast growth factor-23 (FGF-23) inhibits sodium-dependent phosphate transport in brush border membrane vesicles derived from hormone-treated kidney slices of the mouse and in mouse proximal tubule cells by processes involving mitogen-activated protein kinase (MAPK) but not protein kinase A (PKA) or protein kinase C (PKC). By contrast, phosphate transport in brush border membrane vesicles and proximal tubule cells from sodium-hydrogen exchanger regulatory factor-1 (NHERF-1)-null mice were resistant to the inhibitory effect of FGF-23 (10(-9) m). Infection of NHERF-1-null proximal tubule cells with wild-type adenovirus-GFP-NHERF-1 increased basal phosphate transport and restored the inhibitory effect of FGF-23. Infection with adenovirus-GFP-NHERF-1 containing a S77A or T95D mutation also increased basal phosphate transport, but the cells remained resistant to FGF-23 (10(-9) m). Low concentrations of FGF-23 (10(-13) m) and PTH (10(-11) m) individually did not inhibit phosphate transport or activate PKA, PKC, or MAPK. When combined, however, these hormones markedly inhibited phosphate transport associated with activation of PKC and PKA but not MAPK. These studies indicate that FGF-23 inhibits phosphate transport in the mouse kidney by processes that involve the scaffold protein NHERF-1. In addition, FGF-23 synergizes with PTH to inhibit phosphate transport by facilitating the activation of the PTH signal transduction pathway.
Highlights
Fibroblast growth factor-23 (FGF-23) and PTH inhibit phosphate transport in renal proximal tubules
Fibroblast growth factor-23 (FGF-23) inhibits sodium-dependent phosphate transport in brush border membrane vesicles derived from hormone-treated kidney slices of the mouse and in mouse proximal tubule cells by processes involving mitogenactivated protein kinase (MAPK) but not protein kinase A (PKA) or protein kinase C (PKC)
In studies focused on the mechanism by which FGF-23 inhibits renal phosphate transport, Yamashita et al in proximal tubule-like OK cells and Baum et al in isolated perfused rabbit proximal tubules demonstrated that high concentrations of FGF-23, concentrations that approximate serum levels in patients with FGF-23 producing tumors, inhibit phosphate transport [8, 9]
Summary
FGF-23 and PTH inhibit phosphate transport in renal proximal tubules. Results: FGF-23-mediated inhibition requires the PDZ-domain adaptor protein NHERF-1 and synergizes with PTH. Fibroblast growth factor-23 (FGF-23) inhibits sodium-dependent phosphate transport in brush border membrane vesicles derived from hormone-treated kidney slices of the mouse and in mouse proximal tubule cells by processes involving mitogenactivated protein kinase (MAPK) but not protein kinase A (PKA) or protein kinase C (PKC). These hormones markedly inhibited phosphate transport associated with activation of PKC and PKA but not MAPK These studies indicate that FGF-23 inhibits phosphate transport in the mouse kidney by processes that involve the scaffold protein NHERF-1. Our current results indicate that NHERF-1 is required for FGF-23 to inhibit phosphate transport, the involvement of Ser and Thr differed between the hormones Given both the differences in the signal transduction pathways and the involvement of the modifiable residues Ser and Thr, we extended the experiments to determine whether PTH and FGF-23 interact with one another in the regulation of phosphate transport in the renal proximal tubule. The results indicate that combining low doses of PTH and FGF-23, doses that individually do not affect phosphate transport, results in marked inhibition of phosphate transport
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