Fibroblast growth factor-23 (FGF23) is a hormone secreted from osteoblasts and osteocytes in response to elevated
extracellular phosphate and vitamin D. Binding of FGF23 to FGF receptors on target cells requires the co-receptor
Klotho. FGF23 downregulates renal proximal tubular reabsorption of phosphate, and inhibits renal synthesis of the
vitamin D hormone through suppression of the renal 1α-hydroxlase. The exact mechanism by which FGF23
suppresses proximal tubular membrane expression of sodium-phosphate cotransporters is not known. In addition, the
physiological role of the putative suppressive effect of FGF23 on parathyroid hormone secretion is currently
unclear, and it has always been an enigma why FGF23 does not lower serum calcium despite suppression of vitamin D
hormone synthesis. Klotho and Fgf23 knockout mice are characterized by severe hypervitaminosis D due to loss of the
suppressive effect on renal 1α-hydroxlase. Therefore, the intricate association between Fgf23/Klotho signaling
and vitamin D metabolism has made it difficult to clearly dissect the vitamin D independent functions of Fgf23 and
Klotho in vivo.
Preliminary data from 9-month-old Fgf23/vitamin D receptor (VDR) compound mutants on a rescue diet enriched with
calcium, phosphorus, and lactose revealed renal calcium and sodium wasting, hyperphosphatemia, and severe secondary
hyperparathyroidism in Fgf23/VDR compound mutants. Further experiments suggested that lack of Fgf23 signaling
through Fgf23 or Klotho deficiency reduced distal renal tubular transport of the fully glycosylated transient
receptor potential vanilloid-5 (TRPV5) channel to the plasma membrane by a mechanism involving with-no-lysine
kinase-4 (WNK4) and serum- and glucocorticoid-inducible kinase-1 (SGK1) in a vitamin D independent fashion. These
data suggest that Fgf23 is not only a phosphaturic but also a calcium-conserving hormone, and suggest crosstalk of
Fgf23 and aldosterone signaling at the level of SGK1, establishing a novel molecular link between phosphate,
calcium, and sodium homeostasis.
The central aim of the current proposal is to elucidate further the vitamin D independent molecular functions of
Fgf23 and Klotho in the regulation of renal calcium, phosphate, and sodium reabsorption, in the regulation of PTH
secretion, and in disease progression of experimental chronic kidney disease (CKD). Our hypothesis is that Fgf23
signaling directly regulates distal tubular calcium and sodium reabsorption as well as proximal tubular phosphate
reabsorption through the ERK1/2-SGK1 signaling pathway, and that Fgf23 deficiency partially protects against
progression of CKD. To test this hypothesis, we propose in vivo gain-of-function experiments with recombinant FGF23
and acute loss-of-function experiments with anti-FGF23 antibodies in wild-type, VDR, Fgf23/VDR, and Klotho/VDR
mutant mice, as well as in vitro experiments using isolated proximal and distal tubular segments, cultured primary
proximal and distal tubular cells, and cultured primary parathyroid cells from wild-type, Fgf23, Klotho, VDR,
Fgf23/VDR, and Klotho/VDR mutants. The proposed experiments will significantly advance our knowledge about the
molecular role of Fgf23 and Klotho in calcium, phosphate, and sodium homeostasis, as well as in the progression of
CKD. Thus, the proposed work may have important implications for human and veterinary clinical medicine.
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