Phosphaturic action of fibroblast growth factor 23 in Npt2 null mice

Abstract

In the present study, we evaluated the roles of type II and type III sodium-dependent P(i) cotransporters in fibroblast growth factor 23 (FGF23) activity by administering a vector encoding FGF23 with the R179Q mutation (FGF23M) to wild-type (WT) mice, Npt2a knockout (KO) mice, Npt2c KO mice, and Npt2a(-/-)Npt2c(-/-) mice (DKO mice). In Npt2a KO mice, FGF23M induced severe hypophosphatemia and markedly decreased the levels of Npt2c, type III Na-dependent P(i) transporter (PiT2) protein, and renal Na/P(i) transport activity. In contrast, in Npt2c KO mice, FGF23M decreased plasma phosphate levels comparable to those in FGF23M-injected WT mice. In DKO mice with severe hypophosphatemia, FGF23M administration did not induce an additional increase in urinary phosphate excretion. FGF23 administration significantly decreased intestinal Npt2b protein levels in WT mice but had no effect in Npt2a, Npt2c, and DKO mice, despite marked suppression of plasma 1,25(OH)(2)D(3) levels in all the mutant mice. The main findings were as follow: 1) FGF23-dependent phosphaturic activity in Npt2a KO mice is dependent on renal Npt2c and PiT-2 protein; 2) in DKO mice, renal P(i) reabsorption is not further decreased by FGF23M, but renal vitamin D synthesis is suppressed; and 3) downregulation of intestinal Npt2b may be mediated by a factor(s) other than 1,25(OH)(2)D(3). These findings suggest that Npt2a, Npt2c, and PiT-2 are necessary for the phosphaturic activity of FGF23. Thus complementary regulation of Npt2 family proteins may be involved in systemic P(i) homeostasis.

Renal-specific and inducible depletion of NaPi-IIc/Slc34a3, the cotransporter mutated in HHRH, does not affect phosphate or calcium homeostasis in mice

“…5). Both PTH and FGF23 are downregulated in Slc34a1-deficient mice, consistent with the reduced plasma levels of P i in these animals (3,38), whereas FGF23 but not PTH is reduced in Slc34a3 constitutive knockouts (30). Consistently with the absence of changes in the expression of NaPi-IIa in renal BBM, we found that both PTH (Fig.…”

“…In addition to these indirect approaches, constitutive depletion of Slc43a1/NaPi-IIa in mice results in hypophosphatemia associated with renal P i wasting (3), even though the expression of NaPi-IIc in the proximal microvilli is upregulated (37). PTH and FGF-23 are reduced in Slc43a1/NaPi-IIa-deficient mice, whereas 1,25(OH) 2 D 3 is increased, resulting in high circulating and urinary Ca 2ϩ (3,38). In contrast, the constitutive depletion of Slc34a3/NaPi-IIc does not lead to either hypophosphatemia or hyperphosphaturia, although mutant mice exhibit elevated 1,25(OH) 2 D 3 associated with hypercalcemia and hypercalciuria (30).…”

Interactions between calcium and phosphorus in the regulation of the production of fibroblast growth factor 23 in vivo

“…FGF23 is expressed in and released from osteoblasts and osteocytes in response to hyperphosphatemia and 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] (19,20,39). In the renal tubule, FGF23 binds to FGF receptors and their cofactor Klotho, causing inhibition of the expression of the sodiumdependent phosphate cotransporters Npt2a and Npt2c, thereby resulting in less renal phosphorus reabsorption (11,21,35,40,41). In addition, FGF23 inhibits expression of the 1␣-hydroxylase enzyme, leading to less formation of 1,25(OH) 2 D 3 (28,35,37,38).…”

Post-transcriptional regulation of the Type IIA sodium-phosphate cotransporter by parathyroid hormone.

“…FGF23 is secreted from the bone and is another potent phosphaturic hormone that in conjunction with Klotho decreases the renal transport maximum for phosphate by decreasing the abundance of Npt2a and Npt2c, as well as PiT-2, in the BBM of the proximal tubule 52 . Klotho is the co-receptor for FGF23, and also circulates as an endocrine factor to promote anti-aging systemic effects 54 .…”