Fibroblast growth factor-23 (FGF23) is a phosphaturic hormone that contributes to several hypophosphatemic disorders by reducing the expression of the type II sodium-phosphate cotransporters (NaPi-2a and NaPi-2c) in the kidney proximal tubule and by reducing serum 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] levels. The FGF receptor(s) mediating the hypophosphatemic action of FGF23 in vivo have remained elusive. In this study, we show that proximal tubules express FGFR1, -3, and -4 but not FGFR2 mRNA. To determine which of these three FGFRs mediates FGF23's hypophosphatemic actions, we characterized phosphate homeostasis in FGFR3(-/-) and FGFR4(-/-) null mice, and in conditional FGFR1(-/-) mice, with targeted deletion of FGFR1 expression in the metanephric mesenchyme. Basal serum phosphorus levels and renal cortical brush-border membrane (BBM) NaPi-2a and NaPi-2c expression were comparable between FGFR1(-/-), FGFR3(-/-), and FGFR4(-/-) mice and their wild-type counterparts. Administration of FGF23 to FGFR3(-/-) mice induced hypophosphatemia in these mice (8.0 +/- 0.4 vs. 5.4 +/- 0.3 mg/dl; p < or = 0.001) and a decrease in renal BBM NaPi-2a and NaPi-2c protein expression. Similarly, in FGFR4(-/-) mice, administration of FGF23 caused a small but significant decrease in serum phosphorus levels (8.7 +/- 0.3 vs. 7.6 +/- 0.4 mg/dl; p < or = 0.001) and in renal BBM NaPi-2a and NaPi-2c protein abundance. In contrast, injection of FGF23 into FGFR1(-/-) mice had no effects on serum phosphorus levels (5.6 +/- 0.3 vs. 5.2 +/- 0.5 mg/dl) or BBM NaPi-2a and NaPi-2c expression. These data show that FGFR1 is the predominant receptor for the hypophosphatemic action of FGF23 in vivo, with FGFR4 likely playing a minor role.

Prenatal administration of dexamethasone causes hypertension in rats when they are studied as adults. Although an increase in tubular sodium reabsorption has been postulated to be a factor programming hypertension, this has never been directly demonstrated. The purpose of this study was to examine whether prenatal programming by dexamethasone affected postnatal proximal tubular transport. Pregnant Sprague-Dawley rats were injected with intraperitoneal dexamethasone (0.2 mg/kg) daily for 4 days between the 15th and 18th days of gestation. Prenatal dexamethasone resulted in an elevation in systolic blood pressure when the rats were studied at 7-8 wk of age compared with vehicle-treated controls: 131 +/- 3 vs. 115 +/- 3 mmHg (P < 0.001). The rate of proximal convoluted tubule volume absorption, measured using in vitro microperfusion, was 0.61 + 0.07 nl.mm(-1).min(-1) in control rats and 0.93+ 0.07 nl.mm(-1).min(-1) in rats that received prenatal dexamethasone (P < 0.05). Na(+)/H(+) exchanger activity measured in perfused tubules in vitro using the pH-sensitive dye BCECF showed a similar 50% increase in activity in proximal convoluted tubules from rats treated with prenatal dexamethasone. Although there was no change in abundance of NHE3 mRNA, the predominant luminal proximal tubule Na(+)/H(+) exchanger, there was an increase in NHE3 protein abundance on brush-border membrane vesicles in 7- to 8-wk-old rats receiving prenatal dexamethasone. In conclusion, prenatal administration of dexamethasone in rats increases proximal tubule transport when rats are studied at 7-8 wk old, in part by stimulating Na(+)/H(+) exchanger activity. The increase in proximal tubule transport may be a factor mediating the hypertension by prenatal programming with dexamethasone.

Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone implicated in the pathogenesis of several hypophosphatemic disorders. FGF23 causes hypophosphatemia by decreasing the expression of sodium phosphate cotransporters (NaPi-2a and NaPi-2c) and decreasing serum 1,25(OH)2Vitamin D3 levels. We previously showed that FGFR1 is the predominant receptor for the hypophosphatemic actions of FGF23 by decreasing renal NaPi-2a and 2c expression while the receptors regulating 1,25(OH)2Vitamin D3 levels remained elusive. FIBROBLAST GROWTH FACTOR 23 (FGF23) is a phosphaturic hormone that has been implicated in several inherited and acquired hypophosphatemic disorders (15). FGF23 increases urinary phosphate excretion by decreasing renal brush-border expression of the sodium phosphate cotransporters 2a and 2c (NaPi-2a and NaPi-2c) (14, 42). In addition, FGF23 decreases the expression of 25(OH)Vitamin D-1␣-hydroxylase (CYP27B1) and increases the expression 24-hydroxylase (CYP24) resulting in low-serum 1,25(OH) 2 Vitamin D 3 levels (37, 42). The inherited hypophosphatemic disorders where FGF23 levels are increased include X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, and autosomal recessive hypophosphatemic rickets (12,14,21,24,31,36,50). The increased FGF23 levels in these disorders result in severe hypophosphatemia, rickets/osteomalacia, bone pain, fractures, and growth failure in children. Serum FGF23 levels are also elevated in tumor-induced osteomalacia (8, 9).The FGF family of ligands bind to FGF receptors (FGFRs) to mediate their actions (10,17,23,34). Four FGFRs (FGFR1-4) are encoded by four genes and alternative splicing (b and c isoforms of FGFR1-3) results in tissue and ligand binding specificity (33,35). The proximal tubule, the site of most renal phosphate reabsorption (4, 46) and 25(OH)Vitamin D-1␣-hydroxylase activity (7, 13), has FGFR1, 3, and 4, but it does not express FGFR2 (14).We previously utilized FGFR-null mice with the goal of determining which receptor was responsible for the FGF23-mediated decrease in renal phosphate transport and vitamin D production. In these studies, FGF23 was administered to conditional FGFR1Ϫ/Ϫ , and FGFR4 Ϫ/Ϫ mice. FGFR1 was found to be the predominant receptor mediating the hypophosphatemic actions of FGF23 by decreasing brushborder membrane (BBM) NaPi-2a and NaPi-2c expression with FGFR4 playing an additional but relatively minor role (14). Liu et al. (29) also found that deletion of either FGFR3 or FGFR4 in a mouse model of X-linked hypophosphatemic rickets (Hyp mouse) did not correct the disturbances in phosphate homeostasis. Intriguingly, in the conditional FGFR1 Ϫ/Ϫ mice, as well as FGFR3 Ϫ/Ϫ and FGFR4 Ϫ/Ϫ mice, 1,25(OH) 2 Vitamin D 3 levels decreased comparably after administration of FGF23 (14). This implies that FGF23 regulates proximal tubular 1,25(OH) 2 Vitamin D 3 biosynthesis using a different receptor than for the inhibition of phosphate transport in the proximal tubule. 1,25(OH) 2 Vitamin D 3 is primarily synthesized in the pr...

Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that acts on the proximal tubule to decrease phosphate reabsorption and serum levels of 1,25-dihydroxyvitamin D₃ [1,25(OH)₂ Vitamin D₃]. Abnormal FGF23 metabolism has been implicated in several debilitating hypophosphatemic and hyperphosphatemic disorders. The renal receptors responsible for the phosphaturic actions of FGF23 have not been elucidated. There are four fibroblast growth factor receptors (FGFR); 1-4 with "b" and "c" isoforms for receptors 1, 2, and 3. FGFR1, 3, and 4 are expressed in the mouse proximal tubule, and deletion of any one receptor did not affect serum phosphate levels, suggesting that more than one receptor is involved in mediating the phosphaturic actions of FGF23. To determine the receptors responsible for the phosphaturic actions of FGF23, we studied Fgfr1 (kidney conditional) and Fgfr4 (global) double mutant mice (Fgfr1⁻/⁻/Fgfr4⁻/⁻). Fgfr1⁻/⁻/Fgfr4⁻/⁻ mice have higher FGF23 levels than their wild-type counterparts (108.1 ± 7.3 vs. 4,953.6 ± 675.0 pg/ml; P < 0.001). Despite the elevated FGF23 levels, Fgfr1⁻/⁻/Fgfr4⁻/⁻ mice have elevated serum phosphorus levels, increased brush-border membrane vesicle (BBMV) phosphate transport, and increased Na-P(i) cotransporter 2c (NaPi-2c) protein expression compared with wild-type mice. These data are consistent with FGFR1 and FGFR4 being the critical receptors for the phosphaturic actions of FGF23.